Biomedical subjects
Publications and source records attributed to R L Powles.
A series of 7 patients with granulocytic sarcoma is presented to illustrate its varied clinical picture. In particular, this condition may present with features which suggest a non-Hodgkin lymphoma. The diagnosis will only be made if a high index of suspicion is maintained and special histopathological methods are used. Granulocytic sarcoma should be treated like an acute myeloid leukaemia.
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The bone marrow (BM) and peripheral blood (PB) from 63 patients were assessed for the presence of chromosomal aberrations after bone marrow transplantation (BMT) following total body irradiation (TBI) for leukemia. Forty-one patients showed no abnormalities in either BM or PB, and 22 had aberrations in either BM or PB or both. Only stable aberrations were found in the BM, but both stable and unstable abnormalities were present in the PB, the majority showing only unstable aberrations. Among the 25 patients who had a leukemic relapse, clonal chromosomal abnormalities were found in the BM of 12 out of the 16 cases for whom marrow was studied at the time of the relapse. A statistically significant negative correlation between leukemic relapse and graft versus host disease (GvHD) was found, but the relationships between chromosome damage and leukemic relapse, GvHD, and the pretransplant radiation dose and between the radiation dose and both leukemic relapse and GvHD were not significant.
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Human AML cells from the blood of a series of patients have been implanted subcutaneously into mice immune-suppressed by thymectomy and total-body irradiation. Solid tumours resulted from 18 out of 19 samples and their growth was compared with the proliferation of AML cells in culture. In 17 cases tumours grew to a maximum size and then spontaneously regressed. Cells from one patient produced tumours which did not regress and could be retransplanted into freshly immune-suppressed mice. Cells from a human promyelocytic cell line (HL60) also produced nonregressing and retransplantantable tumours. Normal human mononuclear bone marrow cells implanted s.c. produced a growth pattern similar to that of the majority of AML cells. A second inoculum of AML cells into animals with regressing tumours also produced tumours and thus regression cannot be accounted for on the basis of returning immunity. AML cells placed into short-term suspension culture invariably matured to monocyte/macrophage type cells and/or granulocytic cells as identified by cytochemical staining. However, no correlation was observed between proliferation or maturation of cells in culture, and tumour growth in vivo. Cells derived from disaggregated AML tumours also showed evidence of myeloid differentiation suggesting that tumour regression is due to maturation of leukaemic cells.
Lymphocytotoxic antibodies were studied sequentially in a series of 42 patients with leukemia who received a bone marrow graft. Of these patients, 38% had cytotoxic antibodies before bone marrow transplantation (BMT). After BMT the antibody status changed with time, but 62% of the patients had antibodies at some time after BMT. During the first 10 weeks after BMT, 40% of the patients had antibodies. Thereafter the frequency rose to 50% and remained at that level beyond one year after BMT. In successful grafts the gamma globulins are of donor origin six months after BMT; thus donor B cells are capable of forming lymphocytotoxic antibodies even when the immune system is suppressed by cyclosporine. The antibodies had recognizable HLA specificity in about half the cases before and after BMT. When donor and patient were HLA-identical, HLA specificity did not correspond to donor/recipient antigens. In two cases in which the donor was matched for only one haplotype, antibodies formed by recipient cells, active against donor HLA antigens, were found.
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Acyclovir is an effective treatment for herpes simplex and herpes zoster infections, but it is somewhat limited by low oral absorption. 2-amino-9-[(2hydroxyethoxy)methyl]-9H-purine (BW A515U), a new prodrug of acyclovir, when evaluated in 10 patients with haematological malignancies, was well tolerated, excellently absorbed, and produced high plasma concentrations of acyclovir which were comparable to those with intravenous acyclovir. The plasma concentrations after oral BW A515U were much higher than those after oral acyclovir.
Cyclosporine is a member of a new family of drugs which interfere and modify the biological regulation of the immune system without being cytotoxic and has now been tested extensively in man. Observation of its toxicity in a homogeneous group of 72 patients with acute myeloblastic leukaemia receiving bone marrow transplants serves to illustrate some of the new and unexpected problems that may be seen when BIRM agents start to be tested in the clinic.
Skin biopsies from 3 patients receiving one-haplotype-matched bone marrow grafts have provided a unique opportunity to demonstrate the presence of donor cells in situ using immunohistological techniques and a monoclonal antibody directed against an epitope common to HLA-A2 and HLA-A28 antigens. The infiltrating cells were also analyzed in consecutive tissue sections with a panel of monoclonal antibodies to human leukocyte antigens, T cells, and epidermal Langerhans cells. Most of the infiltrating cells were shown to be T lymphocytes of donor origin, regardless of whether the histological changes were consistant with graft-versus-host disease (GVHD) or were eczematous. Donor T cells were also shown to colonize histologically normal skin soon after transplantation. Epidermal keratinocytes, dermal endothelium, and adnexal structures did not express the donor HLA type (i.e., were host derived) but the origin of the epidermal Langerhans cells could not clearly be established. The data show that donor cells preferentially migrate to certain sites in skin after transplantation and are not always associated with GVHD.
Skin biopsies from leukaemic patients undergoing allogeneic bone marrow transplantations and treated prophylactically with cyclosporin A were analysed using histological, morphometric, and immunohistological techniques. Samples from donors were used to establish normal values. Biopsies taken from recipients two days before grafting were all histologically normal, but on immunohistological staining half of them showed a reduction in the number of epidermal Langerhans' cells and 29% a reduction in T inducer lymphocytes. Thirty two biopsies were taken from patients with rashes at various times after transplantation: 14 showed lichenoid changes consistent with graft versus host disease, three eczematous tissue reactions, two vesicular lesions, and 12 no histological abnormality. One sample showed changes intermediate between the lichenoid and eczematous forms. The numbers of epidermal Langerhans' cells were low during the first few weeks after transplantation and were normal or raised later regardless of histological appearances. Unlike epidermal Langerhans' cells, significant reductions in the numbers of lymphocytes were not seen. Lesions of all histological types contained mixtures of T inducer and T suppressor/cytotoxic cells, although the eczematous and vesicular lesions contained higher proportions of T inducer cells. Epidermal infiltrates invariably contained T suppressor/cytotoxic cells but infiltration of epidermis by T inducer cells occurred only in the presence of normal numbers of epidermal Langerhans' cells. Natural killer cells were not identified. The immunological appearances of the various histological subgroups thus change with time after transplantation.
1 previously untreated patient with plasma-cell leukaemia and 8 patients with myeloma (4 previously untreated) were treated with high-dose melphalan 100-140 mg/m2 iv. All responded to treatment. 3 of the 5 previously untreated patients achieved biochemical and bone-marrow complete remissions.
35 patients were treated for acute myeloid leukaemia or acute lymphoblastic leukaemia with allogeneic bone-marrow grafts from a parent, child, or sibling who was mismatched at the major histocompatibility complex (MHC). 11 of these patients are alive at least 6 months after grafting, 5 of them after more than 2 years. Of the 15 patients aged under 20 at the time of the graft, 8 are alive and well 6 months to 3 years later. Cyclosporin A was given to all patients after grafting. 1 patient died of acute graft-versus-host disease and in 2 other cases this was a major factor in their death. Graft failure caused the death of 2 patients. 4 patients died of recurrent leukaemia. A fatal complication in 12 patients was pulmonary oedema, often associated with convulsions, intravascular haemolysis, and renal failure. Some of these patients had viral or bacterial infections, but in the majority the syndrome was not associated with demonstrable infection. This syndrome, in which the essential lesion appears to be vascular, was much more common in recipients of mismatched than matched grafts. 3 others died from lung disease in which infection was a factor.
One hundred and nineteen patients with leukaemia have received CSA as prophylaxis against acute GVHD following sibling MHC matched (84) or family member mismatched bone marrow transplants (35). four recipients of matched transplants (3%) died of acute GVHD, a marked improvement on our previous results using methotrexate (26 patients; 27% died of GVHD). Thirty-five patients received mismatched transplants, 15 were under the age of 20 years and eight are alive and in remission, the longest survivor being one at 2 1/2 years after transplant.