Biomedical subjects
Publications and source records attributed to M Hayat.
A total alkaloid and two purified alkaloid extracts of Alangium Vitiense were revealed by our experimental screening to be oncostatic on L1210 leukemia and two other lymphoid neoplasias in Mice. They are not active on myelomonocytoid leukemia WEHI3 nor on B16 melanoma.
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The follow-up of the first active immunotherapy (AI) controlled pilot study on acute lymphoid leukaemia (ALL), started in 1962, is reported: seven patients out of 20 are still in first remission and eight of the AI group are still alive between 10 and 13 years later, while all ten controls have relapsed and died. The methodology of this pilot study is discussed, as well as the results of the later AI trials conducted on ALL. In the light of a critical discussion and of the further trials conducted by the authors or published in the literature, the authors conclude that A1 is efficient in ALL and that its use is indicated as, in several trials, it has been as active as maintenance chemotherapy, as it has induced no deaths in 300 patients contrary to maintenance chemotherapy, which has been responsible for 4 to 28% of deaths in patients in complete remission, and as the authors have registered no late relapses after three years in the AI trials, while such relapses appear in most maintenance chemotherapy trials.
RFCNU or (chloro-2-ethyl)-l-(ribofuranosyl-isopropylidene-2', 3' paranitrobenzoate-5')-3 nitrosourea, a new synthetic nitrosourea derivative, which has been shown to have, in mice, among all nitrosourea derivatives tested, the longest maximallly efficient dose interval (MEDI) and which is not immunosuppressive at the smallest dose of MEDI, gave in a phase II trial on digestive tract tumours (at the dose of 400 mg/m2 per month determined by the phase I trial), 30% objective remissions among which 13% were greater than 50%.
The effect of heat-killed Pseudomonas aeruginosa (10 serotypes) on antibody formation, macrophage activation and leukemia growth was investigated in relation to the dose injected and to the time and the route of administration. It appeared that intravenous administration of the preparation (10(9) bacteria per ml) was the most efficient at the dose of 0.1 ml since: 1) it increased the number of PFC against SRBC when injected 10 days before the antigen (higher doses and shorter time intervals resulted either in no modification or an significant inhibition of the PFC response; 2) it induced a slight activation of peritoneal macrophages as measured by their cytostatic activity for tumor cells in vitro, when injected 3 or 7 days before testing whereas higher doses were ineffective; 3) it increased the survival time of leukemic mice when administered 2.5 days before the injection of L1210 tumor cells, and higher doses were also effective in this immunoprophylaxis assay. When the subcutaneous route was used, large doses appeared to be the most effective: 1) potentiation of the PFC response was obtained only when 0.5 or 0.2 ml were given 10 days before the antigen; 2) macrophage activation was demonstrated 7 and 10 days after 0.5 ml; 3) leukemia growth was retared when 0.5 or 0.2 ml was injected 2.5 days prior to L1210 tumor cell inoculation and also when 0.2 and 0.1 ml were injected 7 days before tumor cells. No correlation between macrophage activation and the inhibition of tumor growth could be found.
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Four new nitrosourea derivatives represent an appreciable progress in the treatment and cure of L1210 leukemia. Their therapeutic index is higher than that of CCNU and MeCCNU. Of these compounds, RFCNU may prove the most promising, as its therapeutic index is the highest of those for all the four compounds studied; moreover, unlike the other products, it is not immunosuppressive, whether administered before or after the antigen.
This work presents the results obtained on 24 patients with disseminated lymphosarcoma and reticulosarcoma (stage III and IV) with a cyclic combination chemotherapy which combines adriamycin, epipodophyllotoxin (VM 26), cyclophosphamide and prednisone. The complete remission rate is 58 p.cent of the patients who entered the trial, the response rate is 75 p.cent. Tolerance of the regimen is good in general from the hematological point of view.
18 acute myeloid leukemia patients were submitted to a Phase II active immunotherapy trial. The median duration of complete remission (CRD) (60 weeks) and of survival after remission (SAR) (104 weeks) were longer than those for our historical control groups. However, the CRD and SAR curves were not broken to form a "cure expectancy" plateau, as was the case for acute lymphoid leukemia.
The authors report a ten year study of active immunotherapy using BCG and irradiated allogeneic leukaemic cells in 200 patients. In acute lymphatic leukaemia, 57 out of 168 patients treated in this way remained in primary remission for 18 months to 10 years after active immunotherapy was begun, the relapse rate became low after 18 months and nil after 36 months. The results varied according to prognostic factors: the cytological type, active immunotherapy being above all effective in small cell (microlymphoblastic and prolymphocytic) types with a hope of cure in 50 to 60 p.cent of cases; malignant cellular volume; meningeal deposits. In microlymphoblastic forms the possibility of survival at the 5th year is greater than 90 p.cent. After relapse during active immunotherapy sensitivity to chemotherapy does not seem to be diminished. Trials of active immunotherapy in acute myeloid leukaemia are worthy of further pursuit. The results of active immunotherapy in leukaemic lymphosarcoma show that immunotherapy may be effective in preventing local recurrence, both of tumour as well as in the marrow. Four patients are in apparently complete remission for more than four years. On the basis of these results, trials of active immunotherapy for "residual disease" should be undertaken in the field of cancerology, going beyond the realm of leukaemias.
The present results of our treatment of acute lymphoid leukaemia patients are summarized: 7 out of 20 randomized patients given active immunotherapy after chemoradiotherapy are still in complete remission after periods varying from seven to ten years (compared to none in the control group). The actuarial results on 100 patients show remission and survival curves presenting a plateau between three and five years for a certain percentage, suggesting a possible cure. Several parameters studied in 200 patients indicate that the factors affecting this percentage are age, cytological type, volume of the tumour, and the localization of leukaemic cells in certain areas. Experiments with L1210 leukaemia show that immunotherapy enhances the effect of chemotherapy when administered after chemotherapy but decreases it when administered before, which is in favour of the use of the sequence chemotherapy-immunotherapy clinically.
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In 143 patients with poorly differentiated lymphosarcoma, leukaemic conversion has been observed in 25. The cytological type was prolymphocytic or lymphoblastic or lymphoblastoid (immunoblastic ?). Twenty-five patients were treated with chemo-radiotherapy, followed by active immunotherapy as if they had primary acute lymphoid leukaemia. A complete remission was obtained in 11. Four are still in first complete remission after 4 1/2 years. Among 136 patients suffering from so-called "poorly differentiated reticulosarcoma", 17 became leukaemic. The cells are cytologically very dystrophic and unidentifiable. A remission was obtained in 7 patients but it was of short duration (median 1 1/2 months, longest 7 months).
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