Between 1982 and 1986 51 patients were treated with ciclosporin a (CSA) to prevent graft versus host disease (GvHD) after bone marrow transplantation (BMT). Major side effects of the drug were tremor, hypertension, hepatotoxicity and nephrotoxicity. Acute GvHD 0 degree to II degree occurred in 80% of our patients, and GvHD III degree and IV degree in 20% despite the use of CSA. Two to four days before the onset of GvHD, CSA serum levels were significantly lower on the average in patients who developed GvHD III degree and IV degree compared to the others. Our data indicate that plasma CSA concentrations higher than 250 ng/ml should be achieved to reduce the severity of GvHD after BMT.
Between October 1979 and March 1982, bone marrow transplantations were performed by the Tübingen Group for BMT on 19 patients with acute leukemia in remission and on one patient with chronic myelocytic leukemia in chronic phase. The conditioning regimen consisted of 2 x 60 mg cyclophosphamide/kg and 10 Gy whole-body irradiation with the linear accelerator. The lung dose was limited by shielding to 8 Gy. In 15 patients, the bone marrow cell suspension of the donor was preincubated with antihuman T-cell globulin (AHTCG) for prophylaxis of graft-versus-host disease (GVHD). All patients showed prompt engraftment of donor cells with good hemopoietic function and complete chimerism. Under reverse isolation in sterile units, no severe bacterial or fungal infections were seen in the phase of bone marrow aplasia. Twelve in twenty patients survived between 25 and 900 days. A severe GVHD was seen only in two patients - one after preincubation with AHTCG. One patient died from relapse of his leukemia, another patient had a testicular relapse which was treated with local radiotherapy. Major problems were seen with chronic GVHD (six patients) and infectious complications, most importantly interstitial pneumonia, in the late post-transplant period.
Twenty-one patients with acute leukemia in second to fifth remission were treated with bone marrow transplantation: 19 patients with transplants from HLA-matched siblings and two with transplants from identical twins. Twelve patients survived from 15 to 1,625 days after transplantation: six of 11 in the ALL group and six of 10 in the AML group. Recurrence of leukemia after marrow transplantation occurred in five patients. The cause of death in five patients was infection, in two patients combined with graft-versus-host disease. Long-term disease-free survival can probably be achieved in 30%-35% of all patients with acute leukemia who receive a marrow transplant in second or subsequent remission.
Skin lesions of five patients presenting with acute and chronic Gvhd after bone marrow transplantation were analyzed on frozen tissue sections using selected monoclonal antibodies against various T-cell determinants and HLA-antigens in order to define immunological phenomena characteristic for cutaneous damage seen in various GvHD states. Four of these patients showed marked increase of a certain T-cell subpopulation positive for HLA-D region products in the upper dermis. A considerable number of these T-cells seemed to show cytotoxic reactivity on the basal cell layers of the epithelium and to correlate with the appearance of an OKT4-, OKT8+, HLA-DR+ T-cell subset in the peripheral blood presenting natural killer (NK) cell like activity on various targets. Ia antigen expression on keratinocytes observed in one patient with chronic GvHD could result from a rapid and irregular turnover of epidermal cells affected by continuous stimuli of these T-cells. Further immunological studies on skin biopsies of patients with different states of GvHD and autoimmune diseases may lead to valuable diagnostic criteria for an early and accurate assessment of various skin lesions in patients after bone marrow transplantation.
Bone marrow transplantations were performed on 15 patients (aged 5-39 years) with severe aplastic anaemia. Twelve patients are alive 76-1930 days (median 668 d) after transplantation, with complete haematopoetic recovery. Total-body radiation with 3.6 Gy in four patients, cyclosporin A administration to ten patients and buffy-coat transfusion to nine patients entirely prevented early rejection. Two patients died of pneumonia (aspergillus; varicella-zoster virus), one patient died of bleeding from a splenic-artery aneurysm. In patients under the age of 40 years with severe aplastic anaemia bone marrow transplantation as early as possible after diagnosis is the treatment of choice if HLA-identical siblings are available as donors. In patients over 40 years treatment should at first be tried with antithymocyte globulin.
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