Immunotherapy in the management of acute leukaemia.
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Biomedical subjects
Publications and source records attributed to R L Powles.
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One hundred and seven untreated patients with acute myelogenous leukemia (AML) were admitted to St. Bartholomew's Hospital between the 10th October 1970 and the 31st January 1973. Before receiving drugs to induce remission they were allocated alternatively into 2 groups to decide their remission treatment, a group to receive chemotherapy alone and a group to receive the same chemotherapy with immunotherapy. The patients were then given induction chemotherapy and 45 of them attained complete remission. All patients in remission then received chemotherapy consisting of 5 days treatment every 28 days. Patients receiving immunotherapy were also given multiple weekly intradermal injections of irradiated stored AML cells and Glaxo BCG using a Heaf gun. There were 19 patients in the group which received only chemotherapy during remission; 7 of these patients remain alive (median survival after attaining remission--303 days) and only 5 are still in their first remission (median remission length 188 days). Twenty three patients were allocated to receive immunotherapy during remission in addition to chemotherapy and 16 remain alive (median 545 days) and 8 are in their first remission (median 312 days). The difference in survival of the 2 groups is significant with a sigma value of 0.003.
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Leukaemia cells were collected from the blood of 72 untreated patients using a continuous-flow blood cell separator. The yield of cells was proportional to the number circulating in the patient, and up to 1 x 10(12) could be obtained in three hours. Complications of the procedure were mild, consisting of chills and shivering in 18% of patients. Leucopheresis at the time of diagnosis is an essential part of setting up a specific immunotherapy programme for patients with acute myelogenous leukaemia, and the lack of harmful side effects makes the collection of these cells ethically justified. The need for a centralized service to provide cells for this form of therapy is emphasized.
Consecutive adult patients admitted to St. Bartholomew's Hospital with acute myelogenous leukaemia have been treated with a remission induction drug schedule consisting of daunorubicin and cytosine arabinoside. Intermittent five-day courses were used in 72 patients, and a complete remission was obtained in 39 patients (54%). An alternative drug schedule in 22 patients resulted in fewer remissions but this may have been due to age differences in the two groups. Age and initial platelet count were found to be important factors in determining the success of remission induction therapy; the older patients and those with low platelet counts responded less well.A series of 23 patients who achieved remissions was divided into two groups; one received intermittent combination chemotherapy as the only form of maintenance, and the other was given weekly immunotherapy in addition to the chemotherapy. The immunotherapy consisted of irradiated allogeneic leukaemic cells and B.C.G. Eight of the 10 patients on chemotherapy alone have already relapsed compared with five out of 13 patients in the immunotherapy group. It is hoped that these promising initial results with this form of maintenance will be confirmed as more patients enter the maintenance trials.
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One hundred and seven untreated patients with acute myelogenous leukaemia (AML) were admitted to St Bartholomew's Hospital between 10 October 1970 and 31 January 1973. Before receiving drugs to induce remission they were allocated alternatively into 2 groups to decide their remission treatment-a group to receive chemotherapy alone and a group to receive the same chemotherapy with immunotherapy. The patients were then given induction chemotherapy and 45 of them attained complete remission. All patients in remission then received chemotherapy consisting of 5 days treatment every 28 days. Patients receiving immunotherapy were also given multiple weekly intradermal injections of irradiated stored AML cells and Glaxo B.C.G. using a Heaf gun. There were 19 patients in the group which received only chemotherapy during remission; 7 of these patients remain alive (median survival after attaining remission 303 days) and only 5 are still in their first remission (median remission length 188 days). Twenty-three patients were allocated to receive immunotherapy during remission in addition to chemotherapy and 16 remain alive (median 545 days) and 8 are in their first remission (median 312 days). The difference in survival of the two groups is significant with a P value of 0·003.
Leukaemia cells in the peripheral blood of nine patients with acute leukaemia were removed and stored. When the patients had been brought into haematological remission these leukaemia cells were cultured with autologous lymphocytes both before and after the patients had been autoimmunized with their own irradiated leukaemia cells. The extent to which the leukaemia cells stimulated the "normal lymphocytes" was increased as the result of autoimmunization.The implications of the use of this test for determining the best regimen for "immunotherapy" in acute leukaemia are discussed.
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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.
Deep fungal infection in recipients of bone marrow transplants remains a significant cause of morbidity and mortality. Prolonged neutropenia is the major factor predisposing patients to invasive fungal disease. Candida and Aspergillus species remain the two most common pathogens. Prophylaxis against these organisms with the oral polyenes nystatin and amphotericin B has been disappointing. Systemic amphotericin B is too toxic for prophylactic use, yet it remains the mainstay of therapy for suspected or established deep fungal infection. Ketoconazole is contraindicated in patients receiving cyclosporine prophylaxis against graft-vs.-host disease and appears effective only in high doses associated relatively commonly with adverse reactions. This paper reviews results of antifungal prophylaxis and discusses new measures and agents likely to be of value in the prevention of fungal infection in bone marrow transplantation.
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