Phase I-II study of aclarubicin for treatment of acute myeloid leukaemia.
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Aclarubicin↗
Biomedical subjects
F de Vassal
Publications and source records attributed to F de Vassal.
A comparative trial of a MAOI, iproniazide, and a polycyclic agent, mianserine, for the search of the most rapidly and frequently active treatment of depressive syndromes in an oncology service.
Many cancer patients of the "Service des Maladies Sanguines et Tumorales" of Hôpital Paul-Brousse, Villejuif, are psychologically studied by: the objective and quantified Szondi test, and in the case a depressive syndrome clinical diagnosis is confirmed, this state is quantified by a quintile questionnaire requiring 25 "yes or no" answers (determined by five grades and five stages), in case an inhibition or/and hysteric component is found, the subjects are submitted to the care of a psychoanalyst. A comparative trial of the MAOI, iproniazide, and the tetracyclic analog, mianserine, has been conducted for the search of the most frequently and rapidly active antidepressant agent among them both. The hypothesis that mianserine is less frequently and rapidly active than iproniazide was drawn from our previous experience of 20 years: thus patients presenting a score less than or equal to 12/25 were given mianserine (20 up to 30 mg/day to be possibly increased according to medical decision), while those presenting a score greater than or equal to 13/25 received iproniazide (50 up to 75 mg/day). The patients who failed with mianserine received iproniazide, while those who failed with iproniazide were supposed to receive mianserine. The registered results are the following: a) out of the 25 patients with major depressive syndromes (score greater than or equal to 13) submitted to iproniazide, 16 (61%) were in complete remission (score at 0/25) and five in partial regression (score decreased by more than half); this makes 21 responses in all, i.e. 80%, obtained between the 10th and the 30th days, which is superior to all placebo responses which have varied in the reliable literature from 13 to 70%; b) out of 18 depressive patients submitted to mianserine, only one had benefited of a complete remission and four of a partial regression at the 30th day, which makes 28% responses. Among the side effects of iproniazide, they were two colon meteorism syndromes, easily corrected by prostigmine, five hyposomnia cases corrected by dipotassium chlorazepate, four anejaculation or delay at ejaculation cases which needed eserine when the patients require their disappearance or attenuation. We did not register either hepatic or hyperthermic or hypertensive complications: this is in good agreement with the true incidences, especially that of hypertensive crisis which could be found in serious and scientifically documented articles, to be 0.3 to 0.5% for their appearance, and 1 per 100,000 for their fatal evolution. Among the side effects of mianserine, we have not registered any of the hepatic, renal and cardiac complications mentioned in the literature.(ABSTRACT TRUNCATED AT 400 WORDS)
Antidepressive Agents, Tricyclic↗
An oriented phase II trial of THP-adriamycin in breast carcinoma.
THP-ADM is a new anthracycline with broad antitumor activity without cardiac toxicity or alopecia in experimental models. Phase I studies had established a proposed dose for phase II trials of 50 mg/m2 every three weeks. This modality gave an insignificant result in breast carcinoma. Cellular pharmacokinetics suggested that a longer time of administration could be more efficient. In this phase II trial oriented to advanced breast cancer, we have used 3 consecutive daily doses of 20 mg/m2/day in monthly cycles with dose escalation in each patient. We have observed 28% partial remissions (PR). Two patients previously treated with adriamycin had PR. Significantly less alopecia and no cardiac toxicity were observed.
Adult↗
Phase I-II study of aclarubicin for treatment of acute myeloid leukemia.
Aclarubicin (ACM) was administered as induction treatment to 40 patients with acute myeloid leukemia (AML) who were either refractory to initial induction chemotherapy or in relapse. Thirty-eight patients with AML, 2-80 years of age (mean +/- SE, 35.0 +/- 3.2), were evaluated during this study. Seventeen of these patients were given ACM after an unsuccessful attempt had been made to attain a complete remission (CR) with various regimens that included doxorubicin or daunorubicin; this group was considered resistant to these drugs. ACM was administered by rapid iv injection. Thirteen patients received a single course of ACM at a daily dose of 10-30 mg/m2 until a maximum total dose of 300 mg/m2 was reached or until unacceptable toxicity appeared. Of these patients, two (15%) attained a CR. The other 25 patients were given 10-day courses of ACM at a daily dose of 15 mg/m2 with 10-day intervals between courses; courses were repeated until the blast cells were cleared from peripheral blood and bone marrow or until progressive disease became evident. With this regimen, 11 patients (44%) attained a CR. The overall CR rate for the 38 patients was 34%. Total doses necessary to achieve a CR ranged from 150 to 600 mg/m2. A CR was attained by six patients who were previously resistant to a regimen containing moderate doses of doxorubicin. The incidence and severity of the toxic effects were related to the dose of ACM administered per course of therapy. The incidence of mucositis, diarrhea, vomiting, and infection in patients who received doses greater than 150 mg/m2/course was significantly higher than that observed in patients who received a dose of 150 mg/m2/course. In the latter patients, toxicity was within acceptable limits. Alopecia was not observed. Three patients had transient T-wave inversion, and reversible atrial flutter developed in one patient. Our results indicate that ACM is a major new drug for the treatment of AML.
Aclarubicin↗
Phase I-II study of aclacinomycin for a treatment of acute myeloid leukemia.
Aclacinomycin A (ACM) was administered for induction treatment to 40 previously treated acute myeloid leukemia (AML) patients. 38 patients aged 2 to 80 years (mean +/- SE, 35.0 +/- 3.2 years) with overt AML were evaluated; of these, seventeen patients were given ACM after an unsuccessful attempt to obtain a complete remission (CR) with various regimens comprising adriamycin (ADM) or daunorubicin (DNR) and were considered resistant to these drugs. Thirteen patients received ACM at a daily dose of 10 to 30 mg/m2 IV bolus until the maximum total dose of 300 mg/m2 per course was reached or until unacceptable toxicity appeared; of these patients, 2 (15%) attained a CR. Twenty-five patients were given 10-day courses of ACM at the daily dose of 15 mg/m2 IV bolus with 10-day intervals between courses; with this regimen 11 patients (44%) attained a CR. The overall CR rate was 34%. Total doses necessary to attain a CR ranged from 150 to 600 mg/m2. CR was attained by 6 patients (35%) of the 17 who were previously resistant to ADM or DNR. The incidence and severity of the toxic effects such as mucositis, diarrhea, vomiting and infection were related to the dose of ACM administered during each course of therapy. However, in patients who received 150 mg/m2 per course the toxicity was within acceptable limits. Alopecia was not observed. Transient T-wave inversion was observed in 3 patients and atrial flutter developed in one patient. Therefore, we conclude that ACM is a new major drug in the treatment of AML.
Aclarubicin↗
The common acute lymphoid leukemia antigen on b cells of chronic lymphoid leukemia and non-Hodgkin's lymphoma.
Fourteen out of 21 non-Hodgkin lymphoma (NHL) and 3/11 chronic lymphoid leukemia cells (CLL) had the common acute lymphoid leukemia antigen (CALLA) All 32 patients had monoclonal B-cell proliferation. The CLL patients had 90% CALLA positive cells while the proportion of their leukemic elements was superior. Lymph-nodes or bone marrow invaded by a B monoclonal tumor cell population of NHL had significantly more CALLA positive cells (42.1 +/- 32.5%) than non-invaded tissues (11.4 +/- 10.3%). In NHL tissues with monoclonal B-cells, lymph-nodes had significantly more CALLA positive cells (56.0 +/- 29.9%) than marrow (23.5 +/- 27.7%). It is well known that the (CALLA) is not specific for ALL. It has been believed to be a differentiation antigen on pre B-cells. The present study confirms that it also occurs on B-cells (2,4,6,7,8,9,10,11).
Antigens, Neoplasm↗
[Aclacinomycin-A in acute leukaemias and leukaemic non-Hodgkin lymphomas (author's transl)].
Aclacinomycine-A (ACM), a new anthracycline derivative, was administered intravenously to 50 patients in doses of 10-30 mg/m2/day for periods of 6 to 30 days. Among the 45 patients who could be assessed, 17 were suffering from acute myeloid leukaemia, 19 from acute lymphoid leukaemia and 9 from non-hodgkin lymphoma. The results confirmed those first published by the authors in 1978 and led them to propose new measures aimed at reducing the toxicity of ACM. Depending on the dosage, complete or partial (more than 50%) remissions were obtained in patients with acute myeloid leukaemia. In the 19 patients with acute lymphoid leukaemia, complete remission was observed in 2 and partial remission in 2. Among the 9 patients with non-hodgkin lymphoma, there was 3 complete and 1 partial remissions. ACM did not produce alopecia and, as predicted by the authors' experimental study on hamsters, did not have major cardiac toxicity. The gastrointestinal toxicity, which had forced a reduction of the total dose in the first trial, proved moderate, even with normal dosage.
Aclarubicin↗
[Treatment of leukemias and lymphomas with interferons: III. Trial treatment of meningeal localizations of acute leukemia and non-Hodgkin's lymphomas with beta interferon administered by the intrathecal route].
Six patients with pure meningeal relapse of acute lymphoblastic leukemia (ALL) (5 patients) or leukemic lymphosarcoma (LS) (non Hodgkin's lymphoma) (NHL) (1 patient) were treated with intrathecal (I.T.) human fibroblastic interferon (IF beta), one vial (1.3 million units) every other day or every day up to remission or failure. Tolerance was excellent in all six patients with no local or general side effects. 5 patients had no improvement of their meningeal blast infiltrations after 5 to 8 injections and were given IT chemotherapy. The sixth patient achieved a complete remission (CR) after 11 injections, and was maintained in CR for eleven months under systemic and IT chemotherapy. IF cannot be proposed as standard treatment for meningeal leukemia, but we may be able to select a population of patients in which it could be indicated. Its combination with methotrexate and arabinoside cytosine, the two agents used IT which are S-dependent, has to be studied for a possible potentiation. Moreover, its good tolerance would permit its use in severe meningeal viral diseases.
Acute Disease↗
[Results of 2 protocols in the treatment of acute lymphoid leukemia in children, according to prognostic factors].
Children with acute lymphoid leukemia (ALL) were treated according to two protocols. A group of 65 patients in which prognostic factors were no taken into account were treated with a combination of vincristine, asparaginase and prednisone to induce remission, followed by neuromeningeal prophylaxis with intraraquideal methotrexate and cranial irradiation with 2400 rads, two years maintenance therapy with 6-mercaptopurine and methotrexate, and then reinforcing chemotherapy, BCG scarification and injection of irradiated leukemic cell. No relapses were observed in the first 4.5 years. After 7.5 year, general survival was of 60 per 100, with 44 per 100 disease-free. A group of ALL children having a good prognosis were treated as indicated but adding adriamycin during the induction of remission and vindesine during the maintenance period. During the first three years no relapses were seen, and the general survival was 82 per 100, including a high proportion of disease-free children.
Antineoplastic Combined Chemotherapy Protocols↗
[Treatment of leukemias and lymphomas by interferons: II. Phase II of the trial treatment of chronic lymphoid leukemia by human interferon alpha+].
Nine patients with chronic lymphoid leukemia (CLL) were treated with subcutaneous human (leukocyte) interferon alpha (IF alpha). In the first part of the study, 7 patients received intermittent 10 day courses, with free intervals of 10 to 15 days and with a rising dose in the same patient from cycle to cycle, if tolerance permits, from 1.5 to 6 X 10(6) units daily. As we observed a decrease of peripheral lymphocytosis with low doses, and as high doses gave more side-effect in the second part of the study, 4 patients (including two who had previously received intermittent courses) were treated for three months or more at a dose of 1.5 X 10(6) units daily. Tumor mass reduction was seen in only three patients, but significant decrease in peripheral lymphocytosis was seen in 7 patients sustained in the continuous treatment group with relapse at treatment discontinuation in one patient and despite continuation in another. Immune monitoring with currently available T, B, NK and macrophage tests, showed, in this population of patients, a very good correlation between NK cell activity and clinical response. Further studies are warranted to determine the best modalities of treatment as well as the population of patients likely to benefit from it, and the possible special respective indications of IF, and of the other treatments of CLL. One can already consider as a reasonable indication CLL presentations with myeloid insufficiency as IF is not myelotoxic, contrary to chemotherapy.
Drug Evaluation↗
Vindesine: a new vinca alkaloid.
Vindesine (VDS) is an analogue of the vinca alkaloids. Its spectrum of antitumoral activity is similar to that of vincristine (VCR), but with milder experimental neurotoxicity, and it inhibits the polymerization of tubulin. Its terminal half-life is 24 h and its plasma clearance is intermediate between those of vinblastine (VLB) and VCR. The maximal tolerated dose is 4-5 mg/m2/week, the dose-limiting toxicity being myelosuppression (nadir by days 7-8 and recovery by days 11-13). It has already been demonstrated as efficient in childhood acute lymphoid leukemia (ALL), non-Hodgkin's lymphoma, blastic crisis of chronic myeloid leukemia, and esophageal carcinoma. It has also shown activity in Hodgkin's disease, breast and germ cell carcinomas, and melanoma. Intolerance is mainly neurologic, with paresthesias, without motor impairment, or hematologic, with leukopenia, and sometimes alopecia, asthenia, and muscle pains. The results are better if the patients have not been treated previously; continuous infusion could be of interest and there appears to be no cross-resistance with its parent VCR, as documented in ALL.
Animals↗
Phase II trial of aclacinomycin in acute leukemia and lymphosarcoma.
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Aclarubicin↗
Splenectomy and karyotypic conversion in chronic myeloid leukaemia.
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Chromosomes, Human, 21-22 and Y↗
Phase-II trial with vindesine for regression induction in patients with leukemias and hematosarcomas.
Vindesine (VDS) has been submitted to a phase-II trial, the results of which were assessed in terms of regression induction. VDS was given weekly IV in doses of 2 mg/m2 on two consecutive days to 59 patients, 55 of whom were evaluable. A high proportion of complete (36%) and over 50% partial regressions were obtained in acute lymphoid leukemias (ALL) (overall response 63%) whatever the perceptible phase, in blastic crisis of chronic myeloid luekemia (55%), and some responses were recorded in lymphosarcoma (40%). No effect has so far been seen in acute myeloid keukemia or in Hodgkin's disease. Malignant neoplasms of the immunoblastic type seem to be particularly sensitive to VDS. Continuous 48 h IV infusion can induce a remission where an IV push administration of the same dose has failed. One remarkable characteristic of VDS is the apparent absence of cross-resistance with VCR: in acute leukemic forms, 55% of patients who failed to obtain remission induction after three weekly injections of VCR (used in combination chemotherapy) achieved a complete or partial remission with VDS. The toxicity was mainly neurologic (paralytic ileus, constipation, paresthesias, loss of reflexes) and hematologic (leukopenia and thrombopenia), and was not more significant than with the other agents: four patients died of infection or hemorrhage.
Acute Disease↗
[Leukaemias and lymphomas treatment by vindesine. Result of a phase II trial in terms of remission induction (author's transl)].
Vindesine is a derivative of vinblastine and of vincristine. A high proportion of remissions were obtained in acute lymphoid leukaemia (6 complete and 1 incomplete remissions in 15 patients), in blastic crisis of chronic myeloid leukaemia, and a few responses have been registered in lymphosarcoma and Hodgkin's disease. Permanent 48 h i.v. infusion may include a remission where i.v. pusch of the same dose has failed. The most remarkable characteristic of vindesine is the absence of cross-resistance with vincristine as documented in acute lymphoid leukaemia.
Adolescent↗
Preliminary results of chemoradiotherapy followed (or not ) by active immunotherapy of stage III and IV lymphosarcoma and reticulosarcoma: correlation of the results with WHO categorization.
One hundred and one patients with advanced (stage III and IV) LS and RS at the first presentation of the disease or on relapse were treated with a regimen combining initial chemotherapy, complementary radiotherapy on "icebergs," supplementary chemotherapy, and finally, active immunotherapy. The overall complete remission rate was about 79% for LS and 73% for RS. About 50% of the patients were still in remission for both diseases after 2 years; 60% with LS were still alive after 2 years and 44% with Rs. This study shows the useful prognostic value of the WHO classification for LS and RS: the prognosis of prolymphocytic (centrofollicular) LS is far better than that of the lymphoblastic type, which is itself better than that of the very poor prognostic immunoblastic type. The prognosis of RS is intermediate between that of the best prognostic type and that of the poorest prognostic type of LS.
Adolescent↗
Preliminary results of chemo-radiotherapy followed or not by active immunotherapy of stage III and IV lymphosarcoma and reticulosarcoma. Correlation of the results with WHO categorisation.
We 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.
Adolescent↗
Pharmacologic factors and manipulation of immunity systemic adjuvants in cancer therapy.
Because of the experimental and clinical studies which have been extensively conducted with bacillus Calmette-Guérin (BCG) as a systemic adjuvant in cancer immunotherapy, we have analyzed the main factors and conditions which determine its beneficial action and have underlined some of these (eg, the dose factor which controls the amplification of suppressor cells which is probably responsible for failures and even the possible tumor-enhancing effect of immunotherapy). Knowing those factors and conditions, we have been able to establish a systematic immunopharmacologic study of systemic immunity adjuvants, which has resulted in the discovery of agents whose actions are more rapid than that of BCG on one or a few populations of cells involved in immunity and which, unlike BCG, do not induce suppressor cell amplification. This amplification may explain the difference in the results obtained with this mycobacterium in various clinical immunotherapy trials in which it was applied differently. It is proposed to combine these mono- or pauc-functional adjuvants in order to try to obtain all of the beneficial effects of BCG without the amplification of suppressor cells.
Adjuvants, Immunologic↗