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Bone marrow transplantation has the potential to correct this defect and has been performed with HLA-matched family members or unrelated persons as donors. One patient had a return of serum IgG1 and IgG3 concentrations to normal but died of an adenovirus infection 84 days after bone marrow transplantation2. Two other patients died 23 and 60 days after bone marrow transplantation as a result of complications of transplantation (unpublished data). All three patients received total-body irradiation and cyclophosphamide before transplantation. Total-body irradiation is associated with substantial long-term side effects,3 and it may not be needed to destroy the deficient immune system of the recipient and provide immunosuppression adequate to allow sustained engraftment. To avoid some of the long-term side effects, a conditioning regimen not involving radiation was used in the patient described here.
Cord blood collected at birth contains 5 to 10 times more marrow progenitor cells than the peripheral blood of older infants or children, and the volume of blood and nucleated cells that can be collected is substantial4,5,6. Cord blood has been successfully transplanted into patients with aplastic anemia and leukemia and has resulted in repopulation of the bone marrow and immune systems6,7,8,9,10,11,12.
We describe a boy with X-linked lymphoproliferative disease in whom the transplantation of cord-blood stem cells from an HLA-identical sibling resulted in a correction of the genetic defect and the hypogammaglobulinemia.
Case Report
The patient was given a diagnosis of X-linked lymphoproliferative disease based on molecular studies and low serum concentrations of IgG (4.40 g per liter) and IgG1 (1.98 g per liter) at the age of two years, after the death of his older brother from infectious mononucleosis16. The patient was treated with intravenous gamma globulin every three weeks. At four years of age he had melena for which no cause was found. Lymph nodes obtained during laparotomy performed to investigate the melena were infected with type B Epstein-Barr virus. A maternal first cousin who had been treated for non-Hodgkin's lymphoma and had hypogammaglobulinemia was also considered to have X-linked lymphoproliferative disease on the basis of these features and molecular studies. The mothers of both children were considered, on the basis of molecular studies, to be carriers of the disease15,16.
At the age of five years the patient was well. His height was 116 cm, his weight 26 kg, and the body-surface area 0.9 m2. Hematologic and immunologic values obtained at that time are shown in Table 1. His blood group was B positive, and the anti-A isohemagglutinin and antihemolysin titers were 1:128 and 1:8, respectively. His HLA type was A2, A26; B38, B44; DRw11, DRw13; DQ3, DQ6.
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The patient received conditioning therapy consisting of 50 mg of cyclophosphamide per kilogram of body weight per day from day 5 to day 2 before transplantation, 150 mg of melphalan per square meter of body-surface area on day 1 before transplantation, and 30 mg of antithymocyte globulin (Atgam, Upjohn) per kilogram on days 5, 3, and 1 before transplantation. Prophylaxis against graft-versus-host disease consisted of methotrexate with folinic acid and cyclosporine17. Granulocyte-macrophage colony-stimulating factor (GM-CSF, Schering-Plough) (5 µg per kilogram per day intravenously) was given on day 1 after transplantation, and this therapy continued until the absolute neutrophil count remained above 1.0 x 103 per cubic millimeter for three consecutive days. Ganciclovir was given from day 7 to day 1 before transplantation and then three times a week from day 21 to day 60. Acyclovir was given from day 0 to day 21, and intravenous immune globulin was continued weekly until day 60.
Methods
DNA linkage analysis based on restriction-fragment-length polymorphism and the polymerase chain reaction (probes DXS10 and DXS37 and AC repeat markers DXS424 and DXS425) were performed as described elsewhere15 to determine the genotype of X-linked lymphoproliferative disease. The accuracy of diagnosis with flanking-marker analysis was greater than 99 percent. These analyses were performed in the patient both before and after transplantation and in a chorionic-villus sample obtained from the potential donor during the pregnancy.
Results
The 59 ml of cord blood, frozen for 42 days, was infused without incident, half of it on the day of transplantation (day 0) and half on day 1; hemoglobinuria did not occur. The patient's course after transplantation was complicated on day 27 by a right-sided convulsion associated with a diastolic blood pressure of 100 mm Hg; no other cause was identified. The patient had diarrhea from day 3 to day 41 after transplantation. Microscopical examination of rectal and jejunal biopsy specimens on day 17 and cultures of these tissues and stool specimens did not identify a pathogen, and there were no features of graft-versus-host disease. On day 18, a major retroperitoneal hemorrhage caused a duodenal obstruction that resolved over a period of two weeks. Grade 1 graft-versus-host disease of the skin (confirmed histologically) developed on day 80 and resolved after treatment with prednisolone. On day 85, diarrhea developed again and persisted intermittently until day 130; no pathogens were identified, and breath hydrogen studies were consistent with lactose intolerance. The diarrhea abated after the introduction of a lactose-free diet. On day 307 the patient was clinically well, was attending school, and had no features of graft-versus-host disease, although he continued to have intercurrent mild infections of the upper respiratory tract and bowel.
The patient's hematologic and other values after transplantation are shown in Table 1. Red-cell transfusions (group A, washed) were given until day 19, and platelet transfusions (group AB) until day 28 after transplantation. A bone marrow aspirate on day 18 showed a left shift in the myeloid series and the presence of erythroid and megakaryocytic precursors. Hematopoietic engraftment was confirmed by a change in blood group from B to AB noted on days 41 and 156. The fetal-hemoglobin level was 19 percent on day 106, 4 percent on day 190, and 3 percent on day 307. Lymphopoietic engraftment was indicated by rising counts of lymphocytes and lymphocyte subsets, and the donor genotype was identified by molecular studies of peripheral-blood lymphocytes. The patient's lymphocyte count, subsets of T, B, and natural killer cells, and serum IgG, IgM, IgG1, and IgG3 concentrations were normal at the most recent measurement, 21 months after transplantation. The correction of the X-linked lymphoproliferative disease was confirmed by normalization of the patient's serum IgG1 concentration and by molecular studies (on days 42, 123, and 230 after transplantation), which showed that the patient's genotype had become that of the donor. Antibody titers to Epstein-Barr virus types A and B remained undetectable.
Discussion
We report a case of hematopoietic and lymphopoietic reconstitution, together with correction of the genotype for X-linked lymphoproliferative disease, after the transplantation of cord-blood stem cells. A conditioning regimen not involving radiation was used, consisting of cyclophosphamide, melphalan, and antithymocyte globulin. This approach was taken to avoid the side effects associated with the use of radiation -- growth retardation, hypothyroidism, cataracts, and risk of cancer3. Since stable engraftment has occurred, this conditioning regimen may be an alternative to the use of regimens that include radiation in similar settings.
Cord-blood transplantation has been performed in patients with Fanconi's anemia and leukemia, with sustained engraftment6,7,8,9,10,11,12. This case report affirms the potential for transplantation of cord-blood stem cells to achieve sustained hematopoietic and lymphopoietic engraftment in patients with X-linked lymphoproliferative disease, thereby extending the potential use of cord-blood transplantation. We used cord blood to avoid subjecting an infant to a bone marrow collection. Although bone marrow has been collected successfully from very young donors,18 there are inherent risks that may be increased with decreasing age and size of the donor19. These risks relate primarily to the blood volume of the donor18. With cord-blood transplantation there is potentially no risk to the infant or the mother, although the cord is clamped earlier than usual. This can lead to a lower level of hemoglobin and therefore of iron in the infant after birth. The mean hemoglobin level of newborns one to three days after cord-blood collection was reported to be 16.7 g per deciliter (10.4 mmol per liter)5.
The data are insufficient as yet to indicate whether cord-blood transplantation is associated with a rate of engraftment similar to that of conventional bone marrow transplantation. In four patients, the absolute neutrophil count reached 0.5 x 103 per cubic millimeter by days 16, 32, 36, and 386,7,8,9,10,12. In our patient, who was treated with GM-CSF, the absolute neutrophil count reached 0.5 x 103 per cubic millimeter by day 16 after transplantation. This rate of engraftment is similar to that in patients undergoing bone marrow transplantation and receiving GM-CSF20,21.
Transplantation in patients with X-linked lymphoproliferative disease has aroused concern about the potential for a reactivation of Epstein-Barr virus and the development of lymphoma. Diseases induced by the Epstein-Barr virus are rare after bone marrow transplantation, with a risk of 0.6 percent22,23,24. Specific risk factors identified are T-cell depletion, the use of CD3 monoclonal antibodies, the use of mismatched donors, and the development of graft-versus-host disease, in which the risk is as high as 10 percent22,23,24. There was no evidence of a reactivation of infection with the Epstein-Barr virus in the three patients who previously received marrow transplants,2 or in our patient. Thus, there is no reason to believe that the risk of such a reactivation after transplantation in patients with X-linked lymphoproliferative disease is greater than the risk after transplantation in patients with any other disease.
In conclusion, we report the successful transplantation of cord-blood stem cells in a patient with X-linked lymphoproliferative disease. This success further expands the role of cord blood in transplantation.
Supported by grants from the Richard Arcus Fund, the Prince Henry Hospital Centenary Research Fund, the Apex Club of Young, and the Lymphoproliferative Research Fund.
We are indebted to the nursing staff members of the Ward C4 Bone Marrow Transplant Unit for their care of the patient, and to Dr. J.C. Mulley for the molecular genetic studies.
Source Information
From the Departments of Haematology, Oncology, and Bone Marrow Transplantation, Prince of Wales Children's Hospital, Sydney, Australia (M.R.V., R.L.-P.-T., V.B., D.F.); the University of New South Wales, Sydney, Australia (M.R.V.); the Institut de Protection et de Surete Nucleaire, Paris (D.T.); the Departments of Pathology and Microbiology, University of Nebraska Medical Center, Omaha (D.P.); and the Hopital Saint Louis, Paris (E.G.). David Purtilo, M.D., is deceased.
Address reprint requests to Professor Vowels at the Prince of Wales Children's Hospital, Randwick, 2031, NSW, Australia.
References
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Related Letters:
Correction of X-Linked Lymphoproliferative Disease by Stem-Cell Transplantation
Ende M., Ende F. I., Vowels M. R., Duffy B., Lam-Po-Tang R., Ford D.
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Full Text
N Engl J Med 1994;
330:1159, Apr 21, 1994.
Correspondence
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