Treatment of severe aplastic anaemia with antilymphocyte globulin or bone-marrow transplantation.

Fifty-three patients with severe aplastic anaemia were admitted to this hospital between January 1976 and June 1980, of whom three arrived in terminal condition and died before treatment for their basic disease could be given. Thus 50 patients were treated and evaluated in a prospective study according to one protocol. Eighteen patients with an HLA-identical sibling underwent bone-marrow transplantation with the aim of achieving haematopoietic chimerism. Thirty-two patients without an HLA-identical sibling were given antilymphocyte globulin with or without an infusion of HLA-haplotype-identical marrow. All these 32 patients received low-dose androgens after the procedure. In the first group eight patients (44%) survived. In the two other groups, 22 patients survived (69%), of whom 20 were completely self-sustaining (63%). Engraftment and graft-versus-host disease did not occur in the group who received antilymphocyte globulin and haploidentical marrow, and the haematopoietic reconstitutions in these patients were all autologous. These results confirm the efficacy of antilymphocyte globulin in the treatment of severe aplastic anaemia and show that such treatment is at least as good as bone-marrow transplantation. Its mechanism of action remains unknown, but most patients with aplastic anaemia have a pool of haematopoietic stem cells able to repopulate the marrow after this type of treatment.     

Allogeneic bone marrow transplantation for leukaemia and aplastic anaemia. Results of the Leipzig BMT Group

In acute leukaemias there was a stable plateau in the survival curve at 45% after two years if grafted in first complete remission (n = 20) but only 13% of the patients are disease-free alive if grafted in a more advanced stage of the disease (n = 8). In 16 patients transplanted for chronic myeloid leukaemia the overall survival is 40%, in cases with graft-versus-host disease (GVHD) prevention by cyclosporine survival rate could be improved. Only 8 patients with severe aplastic anaemia, partially in low performance status were able to be transplanted; three died of infections, another by acute GVHD. The fatal complications in our study characterize the international well-known major problems in BMT: GVHD, interstitial pneumonitis, infections, graft failure in aplastic anaemia and recurrence of leukaemia, especially in more advanced leukaemia stage.     

Marrow transplantation for severe aplastic anemia associated with exposure to quinacrine

Severe aplastic anemia developed in a patient after administration of quinacrine for treatment of discoid lupus erythematosus. Marrow transplantation was performed from an HLA genotypically identical sister after conditioning with cyclophosphamide. Quinacrine which was accumulated in the patient tissues did not interfere with engraftment, suggesting that the drug has no direct cytotoxic effect on hematopoietic stem cells. This study extends our previous observation that severe aplastic anemia acquired after exposure to drugs or toxins can be cured by marrow transplantation.     

Registry of unrelated bone marrow donors.

Reports of successful transplantation of bone marrow obtained from unrelated donors who were histocompatibility leukocyte antigen (HLA) identical prompted the Canadian Red Cross Blood Transfusion Service in Ottawa to assess the possibility of developing a bone marrow donor registry in Canada. We sent a pamphlet that explained the program to 1568 people who had undergone apheresis and asked them to reply, stating their interest. At the same time the pamphlets and a poster were placed in the blood donor clinic. We received 1232 replies (78.6%) from the apheresis donors, 838 (68.0%) of which indicated a willingness to attend information sessions. Of the 7158 people who gave blood during the 3-month study period, 225 (3.1%) were interested. At the time this paper was written 47 information sessions had been held, and 721 people had attended, 624 (86.5%) of whom had signed a consent form. This indicates a clear interest in a bone marrow donation program. We believe that the ethical issues are overcome by requesting the donation before identification of any patient. From our experience a national registry of unrelated donors seems feasible, and steps are being taken to implement such a program.     

Recruiting unrelated donors for the National Marrow Donor Program

Medical advances have made bone marrow transplantation the treatment of choice for certain hematologic diseases. For those patients eligible for a marrow transplant only about 30 percent find an HLA-compatible match within their families. Studies indicate that unrelated volunteers are willing to donate their marrow. The National Marrow Donor Program was formed in 1986 as a result of a federal contract. This group is a network of donor centers, transplant centers, and collection centers. The Connecticut Red Cross Blood Services is one of approximately 70 donor centers. Recruitment methods vary with each donor center, depending on the resources available. The Connecticut Red Cross Blood Services has recruited more than 1,000 volunteers for entry into the National Marrow Donor Program.     

Mapping of susceptibility and protective loci for acute GVHD in unrelated HLA-matched bone marrow transplantation donors and recipients using 155 microsatellite markers on chromosome 22

Despite matching donors and recipients for the human leukocyte antigens (HLAs) expressed by the major histocompatibility genomic region of the short arm of chromosome 6, several recipients still develop acute graft-versus-host disease (aGVHD) after bone marrow transplantation (BMT). This is possibly due to non-HLA gene polymorphisms, such as minor histocompatibility antigens (mHas) and genes coding for cytokines. However, a detailed genetic background for aGVHD has not yet been established. To find novel susceptibility and/or protective loci for aGVHD, a whole genome-wide association study of donors and recipients needs to be performed. As the first step to such a study, we retrospectively analyzed polymorphisms of 155 microsatellite markers spread across the long arm of chromosome 22 in 70 pairs of HLA-matched unrelated BMT donors and recipients. We performed individual typing and then compared the markers’ allele frequencies (1) between all the aGVHD (grades III and IV GVHD) and GVHD-free (grade 0 GVHD) groups in donors and recipients and (2) between the aGVHD and aGVHD-free groups in donor/recipient pairs that were matched and mismatched for the microsatellite marker’s allele. Screening of the microsatellite markers revealed five loci with a significant difference between the aGVHD and GVHD-free groups and revealed eight loci on chromosome 22, where the microsatellite allele mismatched markers were associated with aGVHD. This screening analysis suggests that several aGVHD-associated susceptible and protective loci exist on chromosome 22, which may encompass novel gene regions that need to be elucidated for their role in aGVHD.     

Restoration of IgA synthesis following transplantation of histocompatible bursa cells into cyclophosphamide treated chicks.

High dose cyclophosphamide (CY) administration to newly hatched Line 6 subline 1 (L6₁) chicks resulted in agammaglobulinemic birds. Monitoring of natural agglutinins to rabbit erythrocytes and immunoglobulin class quantitation by radial immunodiffusion analysis indicated that transplantation with 7-day histocompatible bursal cells partially restored the bursa-dependent immune system, including synthesis of IgA. Additionally, the bursa of Fabricius in this strain of birds appears to be highly susceptible to CY treatment as evidenced by the development of a relatively long-term agammaglobulinemia in > 85% of the CY-treated chicks.