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chain, reported by Hacein-Bey-Abina et al. (April 18 issue),1 is a milestone in medicine. We used a different therapy with a similarly good outcome. X-linked severe combined immunodeficiency was diagnosed in two patients after the initiation of mechanical ventilation for pulmonary failure caused by infections. Immediately after the diagnosis had been made, haploidentical CD34+ peripheral progenitor cells mobilized with granulocyte colony-stimulating factor were isolated to a purity of more than 99 percent.2 These cells were infused with no preparative regimen and no prophylaxis against graft-versus-host disease. Both patients showed signs of T-cell reconstitution beginning three weeks after the CD34+ infusion and were weaned from the ventilator. They are in excellent health, without graft-versus-host disease, 34 and 68 months after transplantation. Patient 1 does not need replacement immune globulin. Patient 2 received a "booster" infusion of CD34+ stem cells from the original donor one year later to improve B-cell function and now receives immune globulin every three months.
Our experience indicates that purified haploidentical CD34+ progenitor cells reconstitute the T-cell compartment and can correct the B-cell defect. Given the possibility of long-term risks3,4 and the availability of effective alternatives, we think that broader application of gene therapy for the treatment of patients with severe combined immunodeficiency or strategies for the correction of persistent B-cell deficiency after successful allogeneic transplantation5 are premature and warrant longer follow-up.
Rupert Handgretinger, M.D., Ph.D.
St. Jude Children's Research Hospital
Memphis, TN 38105
Ewa Koscielniak, M.D.
Olgahospital
70176 Stuttgart, Germany
Dietrich Niethammer, M.D., Ph.D.
Children's University Hospital
72076 Tübingen, Germany
dietrich.niethammer{at}med.uni-tuebingen.de
References
To the Editor: Handgretinger et al. describe two cases of successful haploidentical hematopoietic stem-cell transplantation for X-linked severe combined immunodeficiency. It is indeed known that partially compatible hematopoietic stem-cell transplantation can provide T-cell reconstitution in 70 to 80 percent of cases.1,2 Nevertheless, haploidentical hematopoietic stem-cell transplantation has a number of pitfalls. Despite low numbers of T cells in the graft, graft-versus-host disease does develop in some cases (5 to 10 percent). T-cell repopulation after haploidentical hematopoietic stem-cell transplantation is slow.1,2 A period of more than three months is usually required before T cells can be detected. More important, Patel et al. have reported that after the performance of haploidentical hematopoietic stem-cell transplantation without myeloablation, T-cell immunity declines over time.3 Finally, correction of B-lymphocyte immunity is infrequent in patients with X-linked severe combined immunodeficiency who undergo haploidentical hematopoietic stem-cell transplantation in the absence of myeloablation.1,4 In contrast, so far all patients who have received gene therapy, with a follow-up of more than one year, in whom T-cell immunity has developed do not require intravenous immune globulin therapy. These observations justify further assessment of gene therapy as an alternative to hematopoietic stem-cell transplantation.
The potential risk of gene therapy must not be underestimated and must be balanced against the risk of alternative therapy. The concern of Handgretinger et al. is not entirely appropriate, since helper virus and the expression of a membrane receptor, which accounted for reported toxic effects, are irrelevant to our trial. In our opinion, gene therapy can be considered an option worth exploring for patients with severe combined immunodeficiency.
We would also like to note that on page 1185 of our article, author Lily Leiva's name was misspelled, and the affiliation for Dr. Leiva and author Ricardo Sorensen should have included both Louisiana State University Health Sciences Center and Children's Hospital, New Orleans.
Marina Cavazzana-Calvo, M.D., Ph.D.
Salima Hacein-Bey-Abina, Pharm.D., Ph.D.
Alain Fischer, M.D., Ph.D.
Hôpital Necker–Enfants Malades
75743 Paris CEDEX 15, France
cavazzan{at}necker.fr
References
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