H.E.M. Kay

CYCLOSPORIN A TO PREVENT GRAFT-VERSUS-HOST DISEASE IN MAN AFTER ALLOGENEIC BONE-MARROW TRANSPLANTATION

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.

MISMATCHED FAMILY DONORS FOR BONE-MARROW TRANSPLANTATION AS TREATMENT FOR ACUTE LEUKAEMIA

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.

Encephalopathy in acute leukaemia associated with methotrexate therapy.

Seven patients are described in whom dementia developed during treatment with methotrexate for meningeal leukaemia. The patients presented with confusion, tremor, ataxia, irritability, and somnolence. There were major epileptic fits in two cases and in one case there was progression to coma and death. Necropsy findings in the latter showed infarcted areas in the temporal and parietal lobes, with no evidence of active leukaemic disease or of viral encephalitis. The condition has not responded to radiotherapy and no positive evidence of viral encephalitis has been obtained. On the other hand, when treated with folinic and folic acid the deterioration has been arrested and there has been some improvement; thus the condition appears to be due to methotrexate. The occurrence of so many cases within the past year of a condition not previously described is probably attributable to the introduction of intensive cytotoxic therapy directed against meningeal leukaemia.

FŒTAL THYMIC TRANSPLANT IN A CASE OF DiGEORGE'S SYNDROME

Abstract An infant with the third and fourth pharyngeal pouch syndrome is described. Radiographic evidence of absence of the thymus was strongly supported by tests of immunological function. At 7 months of age thymic tissue acquired from a 13-week foetus was implanted in the rectus abdominis muscle. Immunological data after transplant, as well as the infants ability to resist infection, suggests that immunological function has been reconstituted by transplant of fœtal thymic tissue.

THE PLACE OF BONE-MARROW TRANSPLANTATION IN ACUTE MYELOGENOUS LEUKÆMIA

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.

CYCLOSPORIN A FOR THE TREATMENT OF GRAFT-VERSUS-HOST DISEASE IN MAN

Cyclosporin A was given to five patients with acute leukaemia in whom graft-versus-host disease (G.V.H.D.) had developed after bone-marrow transplantation from sibling donors. In all instances the acute erythematous skin reaction of G.V.H.D. resolved within two days, but four of the five patients died. Cyclosporin A in high doses produced anorexia, nausea, and a reversible rise in blood-urea. The four patients who died all had liver damage, but the histological changes varied. Cyclosporin A modifies the acute skin reaction of G.V.H.D. In the management of liver and gut G.V.H.D., and in prophylaxis of G.V.H.D., its role needs to be determined.

Parenteral acyclovir therapy for herpesvirus infections in man.

Acyclovir is a new antiviral agent which is highly active against herpesviruses in vitro and in laboratory animals. Twenty-three cancer patients with cutaneous and/or systemic herpes zoster or herpes simplex infections were treated with parenteral acyclovir. All had received previous specific treatment for their malignant disease and ten had undergone bone-marrow transplantation. The drug seemed to arrest the progress of the infections and was most effective when given early. Although two patients showed transient increases in blood-urea, possibly the result of acyclovir, the drug was remarkably non-toxic in the doses used.

IMPLANTATION OF A FŒTAL THYMUS, RESTORING IMMUNOLOGICAL COMPETENCE IN A PATIENT WITH THYMIC APLASIA (DiGEORGE'S SYNDROME)

Abstract A 21-month-old male with congenital aplasia of the thymus (DiGeorges syndrome) underwent implantation of thymus fragments from a 16-week-old female foetus. Abnormalities of lymphocyte function as manifested by failure to reject a skin allograft, to develop delayed hypersensitivity to Monilia and dinitrofluorobenzene, or to respond to phytohaemag-glutinin were promptly rectified. There was no evidence of a graft-versus-host reaction.

FACTORS ASSOCIATED WITH INTERSTITIAL PNEUMONITIS AFTER BONE-MARROW TRANSPLANTATION FOR ACUTE LEUKAEMIA

Data from 176 patients with acute leukaemia given allogeneic marrow transplants between Jan. 1, 1977, and Dec. 31, 1980, and reported to the International Bone Marrow Transplant Registry were analysed retrospectively for prognostic factors associated with the development of interstitial pneumonitis (IPn). The overall incidence of IPn was 20% (36/176), and the disease was fatal in 21 of the 36 cases (58%). Three of more than thirty prognostic factors studied seemed to be associated with a low risk of IPn--pretransplant total body irradiation at a dose-rate less than or equal to 5.7 cGy/min, when compared with higher dose-rates (p less than 0.001); post-transplant immunosuppression with cyclosporin-A, when compared with methotrexate (p less than 0.0003); and transplantation of cells from female donors into female recipients (p less than 0.0005). The low dose-rate of total body irradiation and the use of cyclosporin-A were considered as independent variables, but were confounded to the extent that it was not possible to determine if one or both factors were associated with a decreased incidence of IPn.

BONE-MARROW TRANSPLANTATION FOR ACUTE LEUKAEMIA IN FIRST REMISSION

Between 1978 and 1980 133 patients with acute myelogenous leukaemia were given allogeneic bone-marrow transplants from an HLA-identical sibling and were followed up for at least a year. Pre-transplant preparation consisted of high-dose chemotherapy and/or radiation and post-transplant immune suppression consisted of methotrexate or cyclosporin-A. Data for 76 patients transplanted in first transplanted in either second to fourth remission, partial remission, or relapse. The 2-year actuarial survival-rate was 48% (95% CI, 36-60%) for patients transplanted in first remission and 30% 95% CI, 17-43%) for patients with more advanced disease (p = 0.037). Disease status at the time of transplantation was related to the probability of survival (p less than 0.02). The 2-year actuarial leukaemia recurrence-rate was 32% for patients transplanted in first remission and 50% for patients with more advanced disease (p = 0.0017). The probability of remaining in remission also was associated with disease status at time of transplantation (p less than 0.01). The incidence of graft-vs-host disease and interstitial pneumonitis was similar for patients transplanted in first remission and those transplanted later, and methotrexate and cyclosporin A were equally effective in modifying acute GVHD. These data indicate that prolonged survival can be achieved in approximately one-half of patients with acute myelogenous leukaemia given transplants of bone marrow from an HLA-identical sibling during their first complete remission.