P. Pouillart

Two epipodophyllotoxin derivatives, VM 26 and VP 16213, in the treatment of leukemias, hematosarcomas, and lymphomas

The preliminary results obtained with VM 26 and VP 16213 (two semisynthetic derivatives from epipodophyllotoxin) on leukemias and hematosarcomas are described. These compounds are phase M dependent, myelostatic agents whose toxicity can be controlled by intermittent administration. VM 26 proved capable of inducing regression in Hodgkins disease, reticulosarcomas, and lymphosarcomas. Its most remarkable effect was the total regression of neoplastic pleural effusions by systemic administration. VP 16213 seemed to be effective on the same hematosarcomas, but less often. Its most striking action was its oncostatic effect in acute monocytoid leukemia and in the monocytoid component of acute myelomonocytoid leukemia.

Effect of BCG on hematopoietic stem cells: Experimental and clinical study

SummaryIn (DBA/2×C57Bl/6) F1 mice the i.v. injection of 1 mg of living BCG does not increase the total number of CFU/s per femur, but a marked increase in the percentage of CFU/s in S phase is noted as early as the 8th hr. BCG injected i.v. also increases the absolute number of colony-forming units in agar per femur. The effect of BCG appears quite different from the known effect of bacterial endotoxin, and in particular it does not induce a significant increase in the level of CSF. The administration of BCG 24 hrs after treatment with a single dose of 200 mg/kg of cyclophosphamide significantly reduces the time of hematologic restoration, but the same dose of BCG given after a lethal dose of total body irradiation does not increase survival time in mice. These different effects of BCG seem to be related to the role of BCG in stimulating the multiplication maturation pool of the bone marrow without producing any increase in the reserve pool.

Hydroxyurea, Leucopheresis, and Splenectomy in Chronic Myeloid Leukaemia at the Problastic Phase

Forty-three patients with chronic myeloid leukaemia have been treated with hydroxyurea in order to be subjected to leucopheresis for white cell transfusions. Hydroxyurea decreases leucocytosis when it is administered and the blood granulocyte number increases soon after the drug is stopped. The survival of the patients is not different from the survival of the patients treated with conventional chemotherapy (busulphan, mitobronitol) and it is superior to the survival of patients treated with external radiotherapy or with 32P. Half of the patients were subjected to splenectomy during first remission for a phase II trial. They were not randomized, but the distribution according to age was similar in the two groups. A slight difference appears in favour of splenectomy so far as survival is concerned, but there were three post-operative deaths out of 18 patients. We conclude that a phase II trial on the value of splenectomy is indicated ethically, but that the patients should be operated on and nursed in a microbiologically controlled environment.

1975 current results of the first 100 cytologically typed acute lymphoid leukemia submitted to BCG active immunotherapy

SummaryThe first 100 acute lymphoid (and undifferentiated) leukemias, (of which the smears at the first presentation of the disease are still available for typing), treated successively with remission induction chemotherapy, complementary cell-reducing chemoradiotherapy and then active immunotherapy with irradiated pooled allogeneic leukemic cells and fresh Pasteur Institute BCG applied on scarifications, have been reviewed, especially in connection with BCG application.Tolerance of BCG has been good. Its application had to be stopped due to a side effect (choroiditis) in only one patient. This toxic cost is negligible compared to that of so-called maintenance chemotherapy.No subject of our first control trial started in 1963 has relapsed between 3 and 13 years.In the overall group of the 100 patients studied, no relapse has been observed after 48 months, which is quite different to the observations of frequent relapses after that time in patients submitted to maintenance chemotherapy.Moreover, second remissions are obtained in 94% of the patients who relapsed early under immunotherapy, and their life expectancy after a second remission is as high as it is after the first remission.The median of survival is longer than 5 years.The action of active immunotherapy on the immune machinery has been followed by several assays, of which the increase of null cells (which include K-cells) may be the most interesting.Several prognostic factors have been demonstrated among which are sex, the volume of the neoplasia, meningeal localizations, and the cytological types. Age has no prognostic value in immunotherapy patients, contrary to maintenance chemotherapy patients. Also the cytological types behave differently under immunotherapy and under maintenance chemotherapy. The disease-free survival of more than 85% of the microlymphoblastic patients submitted to immunotherapy is not observed in J. Bernards patients submitted to maintenance chemotherapy, which suggests that this high cure rate is due to active immunotherapy. Hence, these prognostic factors are probably factors of sensitivity to active immunotherapy. A statistical computerized study has shown that there is a link between the cytological types and other prognostic factors and that they all depend on the cytological type.Hence, our present protocol is adapted to this immunotherapy sensitivity factor. It comprises a nonrisk preimmunotherapy chemotherapy for the microlymphoblastic type, and a longer and more intensive chemotherapy for less immunotherapy sensitive types.

Attempts at Immunotherapy of 100 Acute Lymphoid Leukemia Patients: Some Factors Influencing Results

There is an extensive literature on experimental active immunoprevention of cancer, which is the stimulation of immune reactions before the establishment of the tumor. This stimulation can be specific, consisting of the administration of irradiated neo-plastic cells, which generally produces a moderate effect [10, 22] or it can be nonspecific, consisting of the application of one or several agents that we have called “systemic immunity adjuvants” (SIA) [13], the most widely used being BCG injected intravenously [2, 4, 21, 26]. A marked effect is generally achieved by a combination of both means. Though the agents are administered by different routes, the effect of combined administration is usually much greater than that of the adjuvant given alone, which is itself superior to that of the irradiated tumor cells (ITC) [21].

Preliminary results of chemo-radiotherapy followed or not by active immunotherapy of stage III and IV lymphosarcoma and reticulosarcoma

SummaryWe treated 101 patients with advanced (stage III and IV) lymphosarcoma and reticulosarcoma at first presentation of the disease or in relapse according to a protocol combining initial chemotherapy, complementary radiotherapy on icebergs, supplementary chemotherapy, and, finally, active immunotherapy.The overall complete remission rate was about 79% for lymphosarcoma and 73% for reticulosarcoma. About 50% of the patients were still in remission in each of the two diseases at 2 years; 60% of lymphosarcoma and 44% of reticulosarcoma patients achieved 2-year survival.This study shows the prognostic value of the WHO classification for lymphosarcoma and reticulosarcoma: the prognosis of prolymphocytic (centrofollicular) lymphosarcoma is far better than that of the lymphoblastic type, which is in turn better than that of the very poor prognosis of the immunoblastic type. The prognosis of reticulosarcoma is intermediate between that of the best-prognosis and that of the poorest-prognosis type of lymphosarcoma.

Comparison of the Combinations a) PDN + VCR°, b) PDN + VCR°→ADMx, c) PDN + VCR°→ADMx→CARx; and d) PDN + VCR + ASP° in Induction of First Remission of Acute Lymphoid Leukemia

Since the introduction of aminopterin 27 years ago, by Farber et al. (1948) (1), a dozen compounds have been made available to which the cells of acute lymphoid leukemia (ALL) are sensitive (see Mathe & Kenis, 1975) (6).

Comparative Results Obtained in the Treatment of Acute Lymphoid Leukemia, Acute Myeloid Leukemia, and Acute Monocytoid Leukemia

Acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML) patients have been treated in our Institute according to different therapeutic principles (Fig. 1). In ALL we have tried to induce remission with chemotherapy, then applied complementary cell-reducing systemic chemotherapy combined with CNS chemoradiotherapy in order to reduce by three or four orders of magnitude the number of leukemic cells left by induction chemotherapy; finally we have submitted the patients to active immunotherapy, which is a combination of the injection of allogeneic leukemic cells and the administration of systemic adjuvants of immunity such as BCG [1, 2].