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In an open study 31 patients undergoing bone marrow transplantation for various haematological diseases received fluconazole as prophylaxis or treatment of fungal infections. In 26 of these patients an antecedent oral prophylaxis with polyene antimycotics had failed to prevent infections with Candida species. Five of the 31 patients received fluconazole as primary prophylaxis because of non-compliance for polyene antimycotics. Fluconazole was administered orally at a daily dose of 100 mg and 200 mg, respectively (n = 29), or intravenously at a dose of 100 mg and 400 mg (n = 2). Cure or efficient prophylaxis was achieved in 22/31 patients (71%) after a median of 52 (9 to 546+) treatment days. In three patients (10%) Candida was eradicated but the infection reappeared 14-28 days after cessation of the drug; in 6 patients (20%) the infection was persistent or progressive. Four patients developed lethal Aspergillus infection while on fluconazole medication. A moderate and reversible elevation of liver function tests under therapy was observed in 9 patients and was possibly attributable to fluconazole in 3 of them (10%). One patient developed tremor which resolved after cessation of fluconazole. No other adverse drug reactions could be noted. We conclude that fluconazole is a relatively safe and effective drug for the prevention and treatment of superficial and, possibly, deep Candida infections in severely immunocompromised patients. It is presumably without preventive value in Aspergillus infections.

In Essen 142 bone marrow transplantations were carried out between December 1975 and February 1985. In 74 cases the indication was acute leukemia in relapse (n = 23) or in first or consecutive remission (n = 51). The conditioning regimen consisted of cyclophosphamide or the combination of cyclophosphamide and total body irradiation. All patients were treated under strict gnotobiotic care. To mitigate the risk of CMV infections, intravenous CMV-hyperimmune globulin and CMV-negative blood products have been applied routinely for 2 years. MTX was used as prophylaxis against GvHD. In the prognostically unfavorable group of acute leukemia in relapse, only one patient showed long-term survival. In this patient, leukemic relapse occurred 6 years after transplantation. The survival rate of AML patients grafted during the first remission is 55% (16/29) with a median observation time of 41 months. For patients grafted in first or consecutive remission of acute lymphoblastic leukemia, the survival rate is 50% (7/14) with a maximal observation time of 34 months. The overall incidence of GvHD in patients at risk was 28% in aplastic anemia, 26% in AML, 9% in ALL, and 63% in CML. In aplastic anemia, no patient developed an interstitial pneumonia. In leukemia, the risk of fatal interstitial pneumonia was 34%.

To determine the influence of advanced age on long-term survival after allogeneic bone marrow transplantation (BMT), the probability of survival and the frequency of transplantation-associated complications were analysed retrospectively in 20 patients with acute leukaemia (AL) or chronic myeloid leukaemia (CML), who were 40-49 years of age (median 44.5 years) at the time of transplant. The results of this patient group were compared to those of 32 patients aged 30-39 years (median 33.5 years) with AL or CML, who also underwent BMT during the same period of time. The overall actuarial survival of the two age groups was comparable with 44% and 41% at 5.9 and 5.6 years, respectively. Patients with standard risk criteria (i.e. HLA-genotypically identical sibling donor, 1st chronic phase of CML or 1st remission of AL) showed a higher probability of survival in both groups (62% at 5.9 years in older patients and 59% at 5.5 years in younger patients, respectively). In contrast, actuarial survival in patients who underwent BMT at an advanced stage of their disease or with marrow from a partially HLA-compatible donor was significantly inferior (P = 0.04). The cumulative incidence of acute and chronic graft-versus-host disease was low in older patients (27%), who received marrow from an HLA-identical sibling donor. The most frequent cause of death was interstitial pneumonia, occurring in seven of the older patients (35%) and in seven of the younger patients (22%). This difference, however, was not statistically significant. Our results indicate that allogenic marrow transplantation in the fifth decade of life might be associated with a tolerable risk of transplantation-related complications. This treatment modality may therefore be regarded as first-line therapy for patients in 1st remission of AL or first chronic phase of CML, who show a normal performance status. The same applies to older patients in advanced stages of disease, since the results are comparable to those achieved in the younger patient group.

A 33-year-old woman underwent bone-marrow transplantation following radiation and chemotherapy for chronic myelocytic leukemia (CML); immunosuppressive therapy was continued for graft-versus-host disease. Five months after successful transplantation, she developed necrotizing retinitis in both eyes with rapid progression over the following weeks. Due to her immunosuppressed state the patient developed pneumonia and died. Postmortem evaluation of the retinal lesions in both eyes disclosed infection by Toxoplasma gondii, which was also found in the brain and myocardium. Multiple viable toxoplasmic cysts were observed at the transition zone from a necrotic to a normal retina. Additionally, cysts of Toxoplasma gondii a normal retina. Additionally, cysts of Toxoplasma gondii were seen in the adjacent intact retina and in areas of necrosis with almost complete absence of retinal or choroidal inflammation. Toxoplasmosis should therefore be considered along with fungi and viruses in the differential diagnosis of necrotizing retinochoroiditis in immunocompromised patients.

Nineteen bone marrow transplant recipients had cytomegalovirus prophylaxis using a commercial hyperimmune globulin. Seronegative donors were selected for blood component substitution. The incidence of seroconversion was 25%. One patient acquired fatal cytomegalovirus associated interstitial pneumonitis. The value of this combined cytomegalovirus prophylaxis in bone marrow transplant recipients in comparison to sole passive immunization is recommended to be the subject of a controlled trial.

Interstitial pneumonitis (IP) is one of the major causes of death following bone marrow transplantation (BMT). This report deals with a comparison between data compiled from six centers concerning the essential factors responsible for the development of IP. Special concern has been paid to the idiopathic form of disease where TBI is thought to be the most important factor in its pathogenesis. Our own experience using different TBI modalities shows that the instantaneous dose rate seems to be an important factor in the development of IIP. Comparing the data from various centers it is not possible at the present time to recommend one optimal modality.

A 20-yr-old man with bulky mediastinal and retroperitoneal tumour masses identified as myeloblastoma is described. After a partial remission was induced by aggressive chemotherapy, mediastinal irradiation and retroperitoneal tumour resection, the patient received an allogeneic marrow graft from his HLA-identical sister. The conditioning regimen consisted of high-dose busulfan and cyclophosphamide. The patient has a well-controlled secondary chronic graft-versus-host disease. He is in unmaintained complete remission and in good general condition at 20 months post-transplantation.

In Essen 121 bone marrow transplantations were carried out. The indications were severe aplastic anemia (n = 18), acute leukemia in relapse (n = 20), acute leukemia in remission (n = 46) or chronic myeloid leukemia (n = 37). The conditioning regimen consisted of cyclophosphamide or the combination of cyclophosphamide and total body irradiation. All patients were treated under strict gnotobiotic care. To mitigate the risk of CMV infections intravenous CMV-hyperimmunoglobulin and CMV-negative blood products have been applied routinely since two years. MTX was used as prophylaxis against GVH-disease. In case of severe aplastic anemia 13 patients (72%) are still alive with a median observation time of 24 months. In the prognostically unfavourable group of acute leukemia in relapse only one patient showed long term survival. In this patient leukemic relapse occurred six years after transplantation. The survival rate of AML patients grafted during the first remission is 55% (15/27) with a median observation time of 40 months. For patients grafted in first or consecutive remission of ALL the survival rate is 42% (5/12) with a maximal observation time of 29 months. Out of 37 patients grafted because of CML, eight were in an advanced stage of the disease. 13 patients are still alive, the maximal observation time is 37 months. The overall incidence of GVHD in patients at risk was 28% in aplastic anemia, 26% in AML, 9% in ALL and 63% in CML. In aplastic anemia no patient developed an interstitial pneumonia. In leukemia the risk of fatal interstitial pneumonia was 34%.

Interferon (IFN-alpha 2 B) was administered to 21 patients with chronic myeloid leukaemia (CML), at an initial dose of 4 X 10(6) IU/m2 daily subcutaneously, adapted to changes in leukocyte count in the course of treatment. Of 16 patients that could be fully evaluated (12 males, 4 females; aged 21-64 years), 15 were in the chronic phase, one had a blast crisis. "Haematological remission" was achieved in nine of the 16 patients, while in the remainder, with one exception, transitory reduction in leukocyte count was obtained. With pretreatment counts of 18-151 X 10(9)/l, normalization to 2.7-6.9 X 10(9)/l was achieved in 13 patients after 3-40 weeks. In parallel to these effects there was a decrease in platelet count (before treatment 86-1550 X 10(9)/l to 30-279 X 10(9)/l after an average of six weeks) and in lactate dehydrogenase (initially 220-958 U/l to 87-232 U/l after 3-33 weeks). A reduction in Philadelphia chromosome-positive metaphases by as much as 50% was observed in four of eight patients. Administration of IFN-alpha 2 B achieved a relatively rapid cell reduction in the chronic phase of CML. The long-term effect on the course of the disease and the place of IFN in the overall concept of CML treatment remains unanswered.

As part of an ongoing phase-I/II trial, 2 patients received a 5-day treatment course with a murine monoclonal antibody (MAB) directed against the human T cell receptor (BMA031) as primary therapy of acute grade III skin and gastro-intestinal graft-versus-host disease (GvHD) occurring after allogeneic bone marrow transplantation (BMT). All MAB infusions were tolerated without side effects. A complete response of all symptoms of acute GvHD could be attained by MAB therapy under a continued baseline immunosuppression with cyclosporin (CSP), and both patients remain alive and disease-free at 7 and 8 months after therapy without evidence of chronic GvHD. Although the exact treatment scheme has still to be defined, we conclude that this MAB may be useful as primary therapy of acute GvHD. However, the potential hazards of 'in vivo' therapy with MABs directed against T lymphocytes call for a critical evaluation of this treatment modality.

An opportunistic infection with Toxoplasma gondii is a rare complication in the immunocompromised host following bone marrow transplantation. In addition to the variability in the clinical picture, difficulty in interpretation of the antibody titers is one of the main obstacles limiting early diagnosis of manifest toxoplasmosis. This report deals with 3 patients out of 86 bone marrow transplant recipients who had manifest toxoplasmosis mainly affecting the central nervous system and cardiac muscle. The clinical picture was that of acute disseminated encephalitis and myocarditis, while the nature of the disease was only disclosed at autopsy.