Paul J. Martin

Probability of finding HLA-matched unrelated marrow donors.

Bone marrow transplantation has become the treatment of choice for certain hematologic diseases. However, only 30–40% of patients who might benefit from this procedure have a suitable family donor. Consequently, many centers have begun to explore the use of unrelated volunteer donors. Initial results have demonstrated the feasibility of this approach. As a result, a national effort has begun to recruit HLA-typed volunteers in order to establish a registry of individuals who would be willing to serve as bone marrow donors. This manuscript explores the potential impact of establishing such a registry. We find that a registry of attainable size could more than double the number of marrow transplants now being performed. However, even with a registry of enormous size, it will still not be possible to identify an HLA-matched donor for some patients.

A phase I-II study evaluating the murine anti-IL-2 receptor antibody 2A3 for treatment of acute graft-versus-host disease.

A murine IgG1 antibody specific for the IL-2-binding site on the human lymphocyte IL-2 receptor β chain (CD25) was evaluated in 11 patients who developed acute graft-versus-host disease following allogeneic marrow transplantation. All patients had received cyclosporine and methotrexate for prophylaxis of GVHD, either alone (4 cases), or in combination with antithymocyte globulin (4 cases) or with prednisone (3 cases). Patients had developed GVHD at 7–53 days (median 12) after transplantation and had failed treatment with corticosteroids for 3–44 days (median 19). Residual GVHD was of grade II severity in 4 patients, grade III in 5 patients, and grade IV in 2 patients. Sequential patients received monoclonal antibody in escalating doses from 0.1 mg/kg/day to 1.0 mg/kg/day for 7 days. Side effects were fever, respiratory distress, hypertension, hypotension, and chills occurring in 11 of 72 (14%) antibody infusions. Trough antibody levels greater than 6 μg/ml were achieved in patients treated with 0.5 or 1.0 mg/ kg/day. Four of eight evaluable patients had an IgM antibody response, and one had an IgG response to the murine immunoglobulin. Clinical response of GVHD was evaluated in 10 patients who received the entire course of the antibody treatment. Among 7 patients treated within 40 days from transplantation, one patient had a complete response in the skin as the only involved organ, and 3 patients had a partial response, 2 in the skin and one in the gastrointestinal tract. No responses were achieved with liver disease at anytime or in any organ in patients treated beyond 40 days after transplantation. Since administration of this antibody was well tolerated and some efficacy was observed in patients with acute GVHD treated early after transplantation, there is a rationale for testing this antibody as an agent for prophylaxis of GVHD.

Long-Term Comparison of Immunosuppressive Therapy with Antithymocyte Globulin to Bone Marrow Transplantation in Aplastic Anemia

Treatment recommendations for aplastic anemia are based on long-term survival data for recipients of syngeneic or allogeneic bone marrow transplants (BMT) and the more recent results of “immunosuppressive therapy” (1ST), which usually includes antihuman thymocyte globulin (ATG) or antihuman lymphoblast globulin (ALG). Patient age and availability of a suitable marrow donor limit the number of patients who are potential candidates for marrow grafting. Many centers will not recommend an allogeneic BMT for patients with aplasia who are over 40 years of age, although some extend the upper age limit to 50 years. Suitable marrow donors include identical twins, genotypically HLA-identical siblings, or phenotypically HLA-identical family members. Transplants using HLA-mismatched family members or phenotypically identical, unrelated donors are usually reserved for “salvage” therapy after failure of a nontransplant treatment regimen.

Studies of T Cell Proliferation Induced by Monoclonal Antibodies of the Second International Workshop

Monoclonal antibodies have proved useful as probes for identifying and studying molecules that mediate or regulate cell function. For example, certain CD3 antibodies are known to activate T cells and cause T cell proliferation (1). These antibodies bind to a noncovalently associated complex of polypeptides with molecular weights between 19,000–28,000 daltons (2–4). The CD3 complex in turn is noncovalently associated with other cell surface molecules that function as antigen receptors for T lymphocytes (5–6). The cross-linking of CD3/T cell antigen receptor complexes by CD3 antibodies is now understood to trigger T cell activation and proliferation in a way that mimics triggering by specific antigen (7). Binding of CD3 antibodies and cross-linking of CD3 on the cell surface can lead to expression of interleukin-2 (IL-2) receptors and secretion of IL-2 into the medium (8).

Retransplantation of marrow and hematopoietic stem cells from normal donors

Transplantation of marrow or hematopoietic stem cells (HSC) from a normal donor requires high-dose marrow ablative conditioning in order to achieve full and sustained engraftment [1]. Graft failure is an uncommon problem following transplantation of marrow from an HLA identical sibling, but occurs more frequently in recipients of marrow from an HLA incompatible donor [2]. Graft failure can have catastrophic consequences, and prolonged pancytopenia may place the patient at high risk of infection or hemorrhage. Although severe graft failure is often fatal, autologous recovery of hematopoiesis can occur in some patients. The absence of donor cells and presence of host lymphoid cells suggests rejection as the cause of graft failure. Severe graft failure refractory to treatment with hematopoietic growth factors is a primary indication for retransplantation. Retransplantation may also be necessitated by recurrence of hematological malignancy. Additional immune suppression is usually necessary before retransplantation, and patients are usually very sensitive to the toxicity of additional conditioning therapy, especially if the time interval after initial transplantation is short. The feasibility of retransplantation and the optimal method depend on the primary disease and the condition of the patient.

Allogeneic and Syngeneic Marrow Transplantation for Aplastic Anemia: Overview of Seattle

Marrow transplantation for the treatment of severe aplastic anemia has to be viewed in the context of alternate therapies for this disease. An earlier study of the International Aplastic Anemia Study Group showed that newly diagnosed patients with severe aplastic anemia treated by supportive therapy with or without androgens had a survival of only 20% at 5 years, with most patients dying within the first 6 months of diagnosis [1]. Most surviving patients had partial or complete spontaneous hematologic recoveries sufficient to live without the need for transfusions. These results were subsequently confirmed by the study group in another cohort of patients [2].