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Postmortem and surgical specimens of liver from 20 patients who had undergone allogeneic bone marrow transplantation for a variety of disorders were examined. The lesions fell into five major categories: bile duct atypia often associated with portal tract fibrosis (8 cases), veno-occlusive disease (2 cases), small foci of non-zonal hepatocyte necrosis (3 cases), opportunistic infections (3 cases), and a miscellaneous group of non-specific abnormalities. Our findings, in conjunction with those in experimental animals, point strongly to the bile duct lesion being a specific manifestation of graft versus host disease (GvHD). Veno-occlusive disease has also been reported recently as a possible manifestation of a graft versus host reaction and, although both our patients with this lesion had evidence of GvHD in the skin and gastrointestinal tract, both had also received irradiation and 6-thioguanine, and these may have been responsible. The foci of hepatocyte necrosis could not be attributed to GvHD with any confidence as the lesion was of only minor severity, infrequent, highly non-specific in appearance and, furthermore, did not correlate well with the presence of bile duct lesions. The absence of specific clinical and biochemical findings in human hepatic GvHD stresses the need for biopsy to make a firm diagnosis. However, the patchy distribution of the bile duct lesion and its absence from the needle biopsies examined in this study suggest possible sampling problems, and further study is necessary to assess its value.

Ninety-six remission patients with acute myelogenous leukemia have been treated with various forms of immunotherapy and chemotherapy in three distinct studies and the clinical outcome of these patients has been reported. In the first study 22 patients were maintained on chemotherapy alone and 28 patients were given the same chemotherapy and additional immunotherapy consisting of BCG and irradiated allogeneic AML cells given at separate sites weekly. It was found that there was a significant increase in survival time of the patients who received immunotherapy (median 510 days) compared with the chemotherapy alone patients (270 days). The p value for this was 0.03. The reason for this prolongation of survival was mainly due to a markedly increased survival time of immunotherapy patients after they relapsed when compared with the chemotherapy patients (165 days compared with 75 days median, p equal to 0.0005). In the second sequential study 24 patients were given immunotherapy alone consisting of irradiated allogeneic AML cells and BCG given at separate sites, and this was compared with unirradiated allogeneic cells and BCG given to 22 patients. There was no difference in the remission length or survival between these two groups. In the third study 13 patients received irradiated cells and BCG as in Study 1 and a further 11 patients received the same immunotherapy but also received a mixture of cells and BCG given during the first three months. There was no difference in the remission and survival of these two groups. The significance of these results is discussed.

In a single-centre prospective trial patients with acute myeloid leukaemia in protective isolation and undergoing remission induction or allogeneic bone-marrow transplantation were randomised to receive one of two prophylactic antibacterial regimens—absorbable co-trimoxazole or non-absorbable neomycin plus colistin. Co-trimoxazole prevented infection more effectively and was associated with less gastrointestinal disturbance, but it may have caused some bone-marrow suppression.

After bone marrow transplantation (BMT), it is important to monitor the bone marrow and lymphoid cell populations of the recipient to document engraftment. When donor and recipient are of unlike sex, the sex chromosomes serve as a useful marker to determine cellular origin. When donor and recipient are of like sex, autosomal heteromorphisms can be used to identify the origin of cells in metaphase. Using Q-banding, we found that 17 of 20 patient/donor pairs (85%) examined showed at least one chromosome heteromorphism that distinguished between recipient and donor cells with certainty. Five of the patients were followed up after BMT in order to document engraftment. Donor metaphases could be detected in the marrow within two weeks of BMT when the graft was successful. Chimaerism was detected in the lymphocyte population even when the graft persisted. In a case of graft failure, donor cells did not persist in the marrow, and the lymphocyte population did not convert to donor type. These studies demonstrate that autosomal heteromorphisms are useful in the study of myeloid and lymphoid chimaeric states after BMT.

28 patients with acute myeloid leukaemia (AML) in first remission were maintained on chemotherapy, consisting of courses of cytosine arabinoside and daunorubicin, and immunotherapy with irradiated AML cells and BCG. The relapse rate and survival rate of these patients were compared with those of a simultaneously treated group of 22 patients in first remission who received sibling bone-marrow transplants after cyclophosphamide (60 mg/kg) given for 2 days and followed by a single dose of 1000 rads total body irradiation. Substantially fewer transplanted patients (4 out of 22) than chemo-immunotherapy patients (19 out of 28) relapsed (p less than 0.005) and 14 (64%) transplanted patients remain alive, well, and disease-free. Survival curves of the two groups of patients show that the transplanted patients never fared worse than the chemo-immunotherapy patients. We suggest that when possible young AML patients in remission should be offered transplantation as an alternative form of treatment.

Summary 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.

In a series of 96 matched sibling bone marrow transplants treated for acute leukaemia, in which the sole prophylaxis against graft versus host disease was cyclosporin given for six months after transplant. Fatal graft versus host disease occurred in 5% of patients,1 although 70% developed the syndrome) and the overall cure rate for this group of patients was approximately 50%.2 There were two major causes of death. The first was a leukaemic relapse rate of approximately 12%,1 and the second was a multiorgan failure syndrome characterised by a vascular endothelial lesion leading to fatal pulmonary oedema in many instances (20%).3 In a series of 35 transplants where the donors were family members mismatched for one haplotype and cyclosporin without purging was used as prophylaxis against graft versus host disease, the incidence of fatal vascular endothelial problems was 35%.3 In this original series marrow engraftment and graft versus host disease were not a major problem.

A study was carried out to assess the effect of total body irradiation on pancreatic and parotid isoenzymes of amylase in patients about to undergo bone-marrow transplantation who had received high-dose cyclophosphamide. Twelve patients were studied, enzyme activity being measured before and at various times after total body irradiation. Serum total amylase activity rose rapidly within 12 hours of irradiation to a maximum at 36 hours, returning to normal by six days; most of the increase was derived from salivary damage, with a much smaller pancreatic component. These results confirm that radiation produces acute changes in amylase activity, which may be of use in assessing radiation-induced damage.

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.

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.

Two groups of patients with acute myeloid leukaemia (AML), treated concurrently, were compared to assess the support required during bone-marrow hypoplasia. One group of patients received drugs to induce initial remission; patients in the other group (in first remission) each received a bone-marrow transplant from a matched allogeneic sib. The patients who received marrow transplants required less time in hospital, were febrile on fewer days, received less therapeutic antibiotic treatment, and had fewer bacterial infections. They also required half as many units of platelets and blood per 100 days. The mean weight-loss per patient was the same in each group, and no patient required intravenous feeding. Transplantation for AML in first remission requires less supportive care than initial remission induction.

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.

Evidence that conventional treatment (chemotherapy and/or immunotherapy) produces a substantial number of cures in acute myeloid leukaemia (AML) is lacking (Powles et al. 1980a). Thomas et al. (1977) showed that there was a proportion of long-term survivors of a group of AML patients treated with high-dose cyclophosphamide, total body irradiation (TBI) and allogeneic bone marrow transplantation (BMT).

In 44 of 56 patients with malignant paraproteinaemia the relationship of serum viscosity, plasma volume (PV), estimated blood volume (BV) and clinical findings was investigated and in the remaining 12 patients one or more of these parameters was studied. There was a correlation between increased PV and serum viscosity (r = 0.66, P less than 0.001). The retinopathy characteristic of the hyperviscosity syndrome (HVS) was always associated with serum viscosity greater than or equal to 3.8 and with hypervolaemia. The evidence that the retinal changes were related more closely to serum hyperviscosity than to hypervolaemia is twofold. First, there was a considerable overlap in the degree of BV expansion, but not serum hyperviscosity, in patients with and without retinopathy. Second, the retinopathy in a patient with Waldenstrom's macroglobulinaemia (WM) improved after plasma exchange with little change in BV. While bleeding was often associated with retinopathy seven patients with multiple myeloma (MM) had no retinopathy, viscosities greater than or equal to 4.3 and BV in the same range as patients with no clinical signs. Haemorrhage in such patients may thus be unrelated to the property of the paraprotein responsible for hyperviscosity. Measurements of PV in a patient with WM having repeated plasma exchanges for bleeding suggested that hypervolaemia may contribute to haemorrhage in some patients. It is suggested that the term 'HVS' should be restricted to patients with retinopathy and that hypervolaemia should be considered a characteristic feature of this syndrome.

Cyclosporin A has been used in conjunction with allogeneic bone-marrow transplantation in the treatment of 23 patients—21 with acute leukaemia, 1 with chronic granulocytic leukaemia, and 1 with aplastic anaemia. The drug was given twice daily from the day before transplant. At the start of the study cyclosporin prophylaxis was stopped in 3 patients within 44 days of transplantation because of non-specific rashes and/or deteriorating renal function. All 3 patients had acute graft-versus-host disease (GVHD) and died. Thereafter the drug was not stopped because of possible toxic manifestations, and 20 patients have been studied (median follow-up 7 months; maximum 13 months). 2 patients have acquired GVHD; 1 patient died of acute GVHD and 1 has chronic mild disease. 3 other patients have died, 2 of recurrent leukaemia and a third of staphylococcal pneumonia with renal failure. Of the remaining patients, 1 has recurrent leukaemia and 1 has moderately severe renal failure. Several toxic effects of cyclosporin A have been observed but they are mostly reversible and no second malignant neoplasm has developed.

Twenty-eight patients with advanced acute nonlymphocytic leukemia, 16 with acute lymphoblastic leukemia, and two with acute undifferentiated leukemia were treated with ICRF-159. No patient achieved a complete remission and only three patients (6%) achieved a partial bone marrow remission. The only significant toxic effect was myelosuppression which probably contributed to the death of six patients. Five patients with acute nonlymphocytic leukemia and one with acute lymphoblastic leukemia received a combination of ICRF-159 and low-dose cytosine arabinoside. There were no remissions in this group and the toxic effects were more marked than with ICRF-159 alone. This study confirms the limited activity of ICRF-159 as a single agent in acute leukemia demonstrated in smaller series, and shows that, when used in combination with low-dose cytosine arabinoside, it was ineffective and resulted in increased toxicity. ICRF-159 alone or in combination with cytosine arabinoside has very limited activity in advanced adult acute leukemia.

A decade ago it seemed reasonable to suppose that all diseases embraced within the general term ‘leukaemia’ were variants of the same fundamental pathological process.

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.

3 observations: malades atteints de neutropenie (au cours de l'evolution d'une leucemie), presentant une infection par Pseudomonas avec ulcerations de la bouche et du pharynx, cellulite de la face, septicemie

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.