Correspondence
Treatment of Severe Combined Immunodeficiency
N Engl J Med 1999; 341:291-292July 22, 1999
- Article
To the Editor:
Buckley and colleagues (Feb. 18 issue)1 deserve recognition for their ongoing contribution to the treatment of patients with severe combined immunodeficiency. It is disappointing, however, that they conclude from this experience that “in utero transplantation of stem cells from related donors does not appear to offer any advantage over transplantation performed soon after birth.” Since in utero transplantation was not compared with postnatal transplantation, this conclusion seems unfounded and premature.
The results of the study performed by Buckley et al. are the best that have been reported for the treatment of severe combined immunodeficiency. Even so, 22 percent of the recipients who did not have HLA-identical donors died. Grade III graft-versus-host disease developed in approximately 10 percent of the patients. In 22 percent of the patients, additional postnatal transplantations were performed to overcome poor B-cell or T-cell function, and 45 of 72 surviving patients required intravenous immune globulin. We reiterate these results not to diminish the tremendous progress detailed in the report by Buckley et al., but to emphasize that there is still room for improvement. The relative efficacy of in utero transplantation remains unknown, largely because of inadequate experience with the approach.
There continue to be potential advantages to in utero transplantation that are not diminished by this report and that can be neither substantiated nor disproved until more data are available. The results of in utero transplantation in our patient with γ-chain deficiency,2 who is now nearly four years old, would compare well with the best results in the series described by Buckley et al. The advantages of in utero transplantation include the reconstitution of T cells before birth, with no postnatal period of susceptibility to infection, and the psychosocial benefits for the mother and family because treatment after birth is not required. Other possible advantages include improved T-cell and B-cell developmental processing and engraftment in the fetal environment, as well as the simplicity of prenatal treatment and the relative cost savings. The assertion by Buckley et al. that “the invasive procedures required for in utero stem-cell transplantation carry risks” cannot be denied, but this should be stated only in the context of the risks associated with postnatal therapy. We have analyzed these risks in detail, and they appear to be relatively minimal.3
3 ReferencesAlan W. Flake, M.D.
Children's Hospital of Philadelphia, Philadelphia, PA 19104Esmail D. Zanjani, Ph.D.
Veterans Affairs Medical Center, Reno, NV 895201
Buckley RH ,Schiff SE ,Schiff RI , et al. Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med 1999;340:508-516
Full Text | Web of Science | Medline2
Flake AW ,Roncarolo M-G ,Puck JM , et al. Treatment of X-linked severe combined immunodeficiency by in utero transplantation of paternal bone marrow. N Engl J Med 1996;335:1806-1810
Full Text | Web of Science | Medline3
Flake AW ,Zanjani ED . In utero hematopoietic stem cell transplantation: a status report. JAMA 1997;278:932-937
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: As Drs. Flake and Zanjani state, we did not compare the outcome of in utero hematopoietic stem-cell transplantation for severe combined immunodeficiency with our results with postnatal transplantation, since to our knowledge, only three successful cases of in utero transplantation for this syndrome have been reported.1-3 Our statement that in utero transplantation for severe combined immunodeficiency appears to offer no advantages over transplantation performed soon after birth was based not on our overall data, which Flake and Zanjani cite, but on the outcomes of transplantations performed early in life. Of the 22 infants who underwent transplantation before 3.5 months of age, 21 (95 percent) have survived. Our opinion was further based on three factors. First, invasive in utero stem-cell transplantation carries additional risks. Second, the mother would probably not be used as the donor, and many infants with severe combined immunodeficiency have transplacentally transferred maternal T cells, which have the potential for a graft-versus-graft reaction against marrow cells from other donors. Third, graft-versus-host disease cannot be detected or treated in utero. Moreover, in utero transplantation would be an option only in cases involving a family history of severe combined immunodeficiency that are diagnosed prenatally. All cases of severe combined immunodeficiency, even those not involving a family history, could be diagnosed at birth on the basis of routine white-cell counts and manual differential counts with cord blood. Stem-cell transplantation could be performed shortly after birth, before the onset of infections. Treatment of infections and management of failure to thrive account for most of the morbidity and cost of postnatal marrow transplantation for severe combined immunodeficiency.
Flake and Zanjani argue that in utero transplantation allows prenatal reconstitution of T cells. However, the infant described in their report had lymphopenia at birth, had a predominance of B cells until he was 5 months old, and did not have in vitro T-cell responses to mitogens that equaled or exceeded those in normal subjects until he was 6 months old (11 months after transplantation).1 These factors suggest that there was an increased risk of opportunistic infection during that time. The patient described by Wengler et al. also had lymphopenia at birth.2 In our series of 89 patients, the recipients of T-cell–depleted marrow began to have normal T-cell function between three and four months after transplantation.
We do not dismiss the applicability of in utero transplantation, but it may be more appropriate for diseases that require ablation with chemotherapy when marrow transplantation is performed after birth, that result in organ dysfunction before birth, or that have poor outcomes with current postnatal treatments.
3 ReferencesRebecca H. Buckley, M.D.
Laurie A. Myers, M.D.
Duke University Medical Center, Durham, NC 277101
Flake AW ,Roncarolo M-G ,Puck JM , et al. Treatment of X-linked severe combined immunodeficiency by in utero transplantation of paternal bone marrow. N Engl J Med 1996;335:1806-1810
Full Text | Web of Science | Medline2
Wengler GS ,Lanfranchi A ,Frusca T , et al. In-utero transplantation of parental CD34 haematopoietic progenitor cells in a patient with X-linked severe combined immunodeficiency (SCIDXI). Lancet 1996;348:1484-1487
CrossRef | Web of Science | Medline3
Flake AW ,Zanjani ED . In utero hematopoietic stem cell transplantation: a status report. JAMA 1997;278:932-937
CrossRef | Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
C Dawson, M A Slatter, A R Gennery. (2005) In utero transplantation: baby steps towards an effective therapy. Bone Marrow Transplantation 36:6, 563-564
CrossRef2
ALAN W. FLAKE. (2002) Genetic Therapies for the Fetus. Clinical Obstetrics and Gynecology 45:3, 684-696
CrossRef3
Laurence E. Shields, Bim Lindton, Robert G. Andrews, Magnus Westgren. (2002) Fetal Hematopoietic Stem Cell Transplantation: A Challenge for the Twenty-First Century. Journal of Hematotherapy <html_ent glyph="@amp;" ascii="&"/> Stem Cell Research 11:4, 617-631
CrossRef
