D. W. Van Bekkum

Results of allogeneic bone marrow transplants for leukemia using donors other than HLA-identical siblings.

PURPOSE To compare outcomes of bone marrow transplants for leukemia from HLA-identical siblings, haploidentical HLA-mismatched relatives, and HLA-matched and mismatched unrelated donors. PATIENTS A total of 2,055 recipients of allogeneic bone marrow transplants for chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), and acute lymphoblastic leukemia (ALL) were entered onto the study. Transplants were performed between 1985 and 1991 and reported to the International Bone Marrow Transplant Registry (IBMTR). Donors were HLA-identical siblings (n = 1,224); haploidentical relatives mismatched for one (n = 238) or two (n = 102) HLA-A, -B, or -DR antigens; or unrelated persons who were HLA-matched (n = 383) or mismatched for one HLA-A, -B, or -DR antigen (n = 108). HLA typing was performed using serologic techniques. RESULTS Transplant-related mortality was significantly higher after alternative donor transplants than after HLA-identical sibling transplants. Among patients with early leukemia (CML in chronic phase or acute leukemia in first remission), 3-year transplant-related mortality (+/-SE) was 21% +/- 2% after HLA-identical sibling transplants and greater than 50% after all types of alternative donor transplants studied. Among patients with early leukemia, relative risks of treatment failure (inverse of leukemia-free survival), using HLA-identical sibling transplants as the reference group, were 2.43 (P < .0001) with 1-HLA-antigen-mismatched related donors, 3.79 (P < .0001) with 2-HLA-antigen-mismatched related donors, 2.11 (P < .0001) with HLA-matched unrelated donors, and 3.33 (P < .0001) with 1-HLA-antigen-mismatched unrelated donors. For patients with more advanced leukemia, differences in treatment failure were less striking: 1-HLA-antigen-mismatched relatives, 1.22 (P = not significant [NS]); 2-HLA-antigen-mismatched relatives, 1.81 (P < .0001); HLA-matched unrelated donors, 1.39 (P = .002); and 1-HLA-antigen-mismatched unrelated donors, 1.63 (P = .002). CONCLUSION Although transplants from alternative donors are effective in some patients with leukemia, treatment failure is higher than after HLA-identical sibling transplants. Outcome depends on leukemia state, donor-recipient relationship, and degree of HLA matching. In early leukemia, alternative donor transplants have a more than twofold increased risk of treatment failure compared with HLA-identical sibling transplants. This difference is less in advanced leukemia.

TRANSPLANTATION OF BONE-MARROW CELLS AND FETAL THYMUS IN AN INFANT WITH LYMPHOPENIC IMMUNOLOGICAL DEFICIENCY

Abstract A 5-month-old male infant with lymphopenic immunological deficiency (Swiss-type agammaglobulinaemia) was treated by transplantation of a fetal thymus, and of bone-marrow-derived cells from his 7-year-old sister. The bone-marrow donor was selected for histocompatibility by leucocyte typing at the HLA locus and by mixed lymphocyte culture. Nucleated bone-marrow cells were centrifuged on an albumin gradient and a small number (5 × 10 6 /kg. body-weight) from the fraction assumed to contain concentrated haemopoietic stem cells, were transplanted. 3 months after the transplantation the boy resumed normal development, and the cellular and humoral immunity were restored. There was an increase in the three major classes of immunoglobulins to a level that exceeded normal adult values. In addition a homogenous IgG-L and an IgA-K band were detected in the serum. A temporary mild exanthema was taken to be a sign of graft-versus-host reaction. Nursing in a laminar-flow cabinet appeared to be relatively simple and highly effective for protection against contamination with microorganisms from the environment.

Conditioning regimens for the treatment of experimental arthritis with autologous bone marrow transplantation

Adjuvant induced arthritis (AA) in Buffalo rats is a chronic progressive disease that responds very well to treatment with myeloablation and rescue with autologous BM. These previous results were obtained by conditioning with a lethal single dose of TBI. In the present study various other conditioning regimens were compared with single dose TBI. Fractionated TBI using adjusted total dose was equally effective. CY and BU when used as single agents at the highest tolerated dose were less effective. Combinations of CY (2 × 60 mg/kg) with lower dose (4 Gy) TBI and of BU with CY were as beneficial as high-dose TBI. These results indicate that a very intense reduction of T lymphocytes, in the order of 3–4 log, is required for obtaining the highest rate of long-lasting complete remissions. A similar conclusion was reached from our studies of various conditioning regimens in rats suffering from experimental allergic encephalitis (EAE). If extrapolated to the clinic, such a degree of T lymphocyte eradication poses upper limits to the number of T lymphocytes that can be safely reintroduced with the autograft. The exact limits cannot be derived from these experiments because the addition of autologous T lymphocytes to the graft yielded different results in the two models of autoimmune disease (AID). Bone Marrow Transplantation (2000) 25, 357–364.Adjuvant induced arthritis (AA) in Buffalo rats is a chronic progressive disease that responds very well to treatment with myeloablation and rescue with autologous BM. These previous results were obtained by conditioning with a lethal single dose of TBI. In the present study various other conditioning regimens were compared with single dose TBI. Fractionated TBI using adjusted total dose was equally effective. CY and BU when used as single agents at the highest tolerated dose were less effective. Combinations of CY (2 × 60 mg/kg) with lower dose (4 Gy) TBI and of BU with CY were as beneficial as high-dose TBI. These results indicate that a very intense reduction of T lymphocytes, in the order of 3–4 log, is required for obtaining the highest rate of long-lasting complete remissions. A similar conclusion was reached from our studies of various conditioning regimens in rats suffering from experimental allergic encephalitis (EAE). If extrapolated to the clinic, such a degree of T lymphocyte eradication poses upper limits to the number of T lymphocytes that can be safely reintroduced with the autograft. The exact limits cannot be derived from these experiments because the addition of autologous T lymphocytes to the graft yielded different results in the two models of autoimmune disease (AID). Bone Marrow Transplantation (2000) 25, 357–364.

Sex-linked thymic epithelial hypoplasia in two siblings: Attempt at treatment by transplantation with fetal thymus and adult bone marrow

Two siblings with thymic epithelial hypoplasia are described. One was treated by transplantation of fetal thymus and adult bone marrow. At autopsy a number of histological changes suggested either graft-versus-host reaction or autoimmune disease in both patients. The significance of these observations are discussed in relation to the pathogenesis of the disease.

Call for case histories of BMT in patients with coincident schizophrenia

Recently, the case for an immune component in the etiology of schizophrenia has regained support,1, 2 leading to randomized controlled trials to explore treatment with immunosuppressive and anti-inflammatory drugs.3 Both postmortem4 and in-vivo studies5, 6 provided indications for an increased proinflammatory status in the brain of patients with recent-onset schizophrenia. A common characteristic of most, if not all, autoimmune diseases (AD) is their favorable response to immunoablation and rescue with BMT. It was established in radiation chimeras more than 50 years ago that the immunological and hematological systems have a common stem cell. In the wake of this discovery came a series of investigations into the role of the BM in autoimmune disorders (AD) demonstrating that both hereditary AD and the susceptibility for induced AD could be transferred by hematopoietic SCTs and that both forms of AD in experimental animals could be cured by an allogeneic BMT from healthy donors.7 We therefore searched among long-term survivors after allogeneic BMT (SCT) for patients with a coexisting AD at the time of the transplant. Up to 1998, case histories of a total of 22 such patients were retrieved, all but one of whom went into CR of their AD.8 These findings did not initiate treatment of AD patients with allogeneic BMT because of the high risks of this procedure. However, after it was demonstrated both in rats with induced systemic arthritis and in rats with an experimental allergic encephalomyelitis (a model for multiple sclerosis) that autologous BMTs were potentially equally effective as allogeneic transplants, this modality has been widely explored for treating refractory AD of all sorts.9 The European Group for Blood and Bone Marrow Transplantation (EBMT) estimates that worldwide around 3000 AD patients had been treated with autologous BMT; 1200 cases were entered in the EBMT database by June 2011.10 Overall, the 5-year survival rate of the first 900 cases analyzed was 85%, with 43% PFS. At present, around 50 000 hematopoietic SCT are registered annually. Considering a conservative prevalence estimate for schizophrenia of 8 per 1000, the registries can be expected to contain data on many survivors with coincident schizophrenia at the time of transplant. Information on the clinical course of schizophrenia after SCT would greatly enhance our understanding of the role of immune processes in schizophrenia. We have therefore asked the EBMT and the Center for Blood and Marrow Transplantation Research (CIBMTR) at the Medical College of Wisconsin about the feasibility of searching their databases for such cases. Simultaneously we call upon hematologists and psychiatrists to inform us directly of their relevant case histories. We are submitting this appeal to the respective professional journals and websites. We think this approach may save time and money in identifying cases that are not into the databases of the international registries. Please send the information about your cases, including identification numbers if registered, to one of us in Utrecht, E-mail: ln.thcertucmu@remmos.i