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Biomedical subjects

A M Stoppa

Publications and source records attributed to A M Stoppa.

At least 91 records · Page 5Linked to original sources
PubMed1992

Pharmacokinetics of mitoxantrone in cancer patients treated by high-dose chemotherapy and autologous bone marrow transplantation.

We have studied the pharmacokinetics of mitoxantrone in cancer patients. Two regimens were used: eight women (10 kinetics) received a 10 min i.v. infusion of 12 mg m-2 of mitoxantrone; seven women (seven kinetics) received high-dose mitoxantrone associated to high-dose alkylating agents and underwent autologous bone marrow transplantation (BMT). High-dose mitoxantrone was administered according to two different protocols. The drug was quantified in plasma with an HPLC assay and pharmacokinetic analysis was performed with the APIS software. Mitoxantrone pharmacokinetics were best described by an open two- (six kinetics) or an open three compartment model (11 kinetics). A large interindivual variability was observed in pharmacokinetic parameters. In the first group of patients, mean +/- s.d. values of clearance, half-life and total distribution volume were 21.41 +/- 14.59 1 h-1, 19.83 +/- 23.95 h, 165.89 +/- 134.75 1 respectively. In the high-dose group, these values were 21.68 +/- 7.30 1 h-1, 50.26 +/- 20.62 h, 413.70 +/- 194.81 1 respectively. Results showed that identification through the open 2-compartment model is certainly related to the small number of late time-points. We therefore think that mitoxantrone pharmacokinetics is generally best described by an open 3-compartment model. Clearance values showed that there was no saturation in mitoxantrone elimination, even at the highest doses. Terminal elimination half-life was probably underestimated because of the lack of late time-points in some kinetics. The half-life is long for patients receiving high-dose mitoxantrone (mean value was 50 h) and it would be hazardous to perform BMT too early after mitoxantrone infusion. Mitoxantrone metabolites were detected in the plasma of five patients receiving high-dose mitoxantrone and in one with hepatic impairment.

Adolescent↗
PubMed1992

Interleukin-2 in association with increasing doses of interferon-gamma in patients with advanced cancer.

Twenty-seven patients with evaluable metastatic cancer were treated with recombinant interleukin-2 (rIL-2) and escalating doses of interferon gamma (IFN-gamma). rIL-2 was infused over a 15 min period at a constant dose (8 x 10(6) IU/m2/8 h x 5 days first cycle, and 8 x 10(6) IU/m2/12 h x 5 days second and third cycles, with 9 days rest between each cycle). IFN-gamma was started 4 days before each cycle of rIL-2 and was given every other day at a dosage of 1 x 10(6) U/m2 x 3/cycle (four patients), 5 x 10(6) U/m2 x 3/cycle (four patients), 5 x 10(6) U/m2 x 5/cycle (four patients) and 10 x 10(6) U/m2 x 5/cycle (15 patients). Common side effects were fluid retention and hepatic toxicity (27 and 15% grade greater than or equal to 2); one ischemic chest pains and one acute respiratory distress occurred. Toxicities were not greater than those described with high dose rIL-2 alone and were similar in each dose level of IFN-gamma. No patient died from the procedure. Four patients responded, one complete response and three partial responses; all were treated with 25 or 50 x 10(6) U/m2/cycle of IFN-gamma (melanoma, two patients; renal cell carcinoma, one patient; lymphoma, one patient). Further phase II studies at these dosages are justified to precisely define the antitumoral efficacy of this association.

Adolescent↗
PubMed1992

Therapy-related acute promyelocytic leukemia: a report on 16 cases.

PURPOSE: To analyze the type of prior tumor and treatment in therapy-related acute promyelocytic leukemia (tAPL) that occurs after chemotherapy and/or radiotherapy (RT), and the hematologic characteristics and outcome of tAPL. PATIENTS AND METHODS: Sixteen patients with tAPL who were gathered during a 10-year period (1982 to 1991) in seven hematologic centers were analyzed retrospectively. RESULTS: There were 13 women and three men. The median age was 46 years (range, 12 to 82). Prior tumor was breast carcinoma in 10 cases, another solid tumor in three cases, and lymphoma in three cases. Two patients had received RT alone, and 14 had received chemotherapy (with RT in 11 cases). Prior chemotherapeutic agents generally included a combination of cyclophosphamide (used for limited periods), fluorouracil (5-FU), vinca alkaloids, and doxorubicin, mitoxantrone, or etoposide (VP16). By contrast, alkylating agents other than cyclophosphamide had been used in only two patients. Median interval between onset of treatment for the prior tumor and diagnosis of APL was 25 months. No patient had a known preleukemic phase. Hematologic and cytogenetic characteristics of the cases of tAPL were identical to those of the usual de novo APL, which included the presence of t(15; 17) in nine of the 10 patients tested. Two patients had early death. Seven patients were treated with intensive chemotherapy, and six achieved complete remission (CR). Three of them subsequently relapsed. Seven patients were treated with all-trans-retinoic acid (ATRA), and four achieved CR through the differentiation of blasts into mature granulocytes. None has relapsed so far. CONCLUSIONS: Our findings suggest that tAPL is not exceptional, and usually has several features in common with other types of therapy-related AML with specific karyotype (ie, t(8;21),t(9;11), inv(16)): solid tumor rather than hematologic malignancy as primary tumor, short interval of development, absence of known preleukemic phase, prior chemotherapy with a combination of several drugs that often included an agent that targets topoisomerase II (doxorubicin or mitoxantrone, but less often VP16). Hematologic characteristics and response to therapy (intensive chemotherapy or ATRA) in tAPL do not seem to differ from those of de novo APL.

Adolescent↗
PubMed1992

Pentoxifylline in vitro reverses neutrophil chemotactic deficiency induced by interleukin-2 treatment.

Patients undergoing immunotherapy with Interleukin-2 experience multiple side effects and are highly susceptible to bacteremia. In a previous study, we confirmed the profound neutrophil chemotactic deficiency induced by Interleukin-2 therapy. Peripheral blood cells exposed to Interleukin-2 in vitro secrete secondary cytokines. The release of tumor necrosis factor into the circulation after Interleukin-2 injection has been proposed as an important mechanism underlying cell function alterations. We tested chemotaxis of neutrophils from normal subjects after incubation with the serum from treated patients. Serums induced a defective chemotaxis of normal neutrophils similar to the one observed with neutrophils from Interleukin-2 treated patients. We have previously demonstrated a dose-dependent reversion of neutrophil chemotaxis after incubation with anti-Tumor Necrosis Factor-alpha antibody. Pentoxifylline is known for counteracting the inflammatory action of tumor necrosis factor. We tested its capability to reverse the chemotactic deficiency of neutrophils induced by treated patient serums. Pentoxifylline was added after incubation of normal cells with patient serum, and the directed chemotaxis was restored. Pentoxifylline may have a significant therapeutic potential for the prevention or treatment of complications related to inappropriately activated neutrophils.

Bacteremia↗
PubMed1991

Influence of mixed chimerism on the results of allogeneic bone marrow transplantation for leukemia.

Serial cytogenetic studies were performed on 60 leukemic recipients of HLA-matched bone marrow transplants (BMT) who were prepared by high doses of alkylating agents and fractionated total body irradiation (TBI). Forty-three patients were recipients of untreated BMT and 17 were recipients of T-depleted BMT. Donor or host mitoses were identified by examination of sex chromosomes in 54 patients or by evaluation of the polymorphism of other chromosomes after specific banding in six patients. Mixed lymphoid chimerism (MLC) was identified in 29 patients and full donor lymphoid chimerism (FDLC) in 29 patients. Complete donor hematopoiesis was recovered in most patients after 12 months, but two T-depleted patients had persistent host cells at 46 and 52 months after the graft. Acute graft-versus-host disease was significantly less frequent in patients with MLC, especially when more than 10% of residual lymphoid cells were detected. The probability of relapse and survival was identical in patients with MLC and FDLC, except in patients with chronic myeloid leukemia where MLC was significantly associated with an increased risk of relapse.

Acute Disease↗
PubMed1991

High-dose recombinant interleukin-2 and acute myeloid leukemias in relapse.

Interleukin-2 (IL-2) is able to induce the regression of metastatic cancers when administered in vivo. IL-2-activated natural killer cells and lymphocytes show, in vitro, activities against leukemic cells. To assess if in vitro observations could have significant clinical relevance, we evaluated the in vivo activity of high-dose recombinant IL-2 (6 to 8 x 10(6) IU/m2/8H intravenous bolus for 5 days) in 10 patients with acute myeloid leukemias (AML) in relapse after chemotherapy (n = 7) or autologous bone marrow transplantation (n = 3). Two patients achieved a complete remission and one had a minimal improvement in his marrow blast cells. Response was observed after one cycle of IL-2 in the two patients achieving a complete remission. These two patients relapsed at 3 and 4 months. These results showing clinical activity of high-dose recombinant IL-2 in AML invite further evaluation of this new form of immunotherapy in other clinical situations, like an adjuvant setting for selected groups of high-risk patients.

Adolescent↗
PubMed1991

Anti-LFA1 monoclonal antibody (25.3) for treatment of steroid-resistant grade III-IV acute graft-versus-host disease.

The in vivo efficacy of 25.3 monoclonal antibody (mAb) directed against human LFA1 molecule was assessed in ten patients with steroid-resistant grade III-IV acute graft-versus-host disease (AGVHD). These patients received non-T-cell-depleted allogeneic bone marrow transplantation for aplastic anemia in two cases and hematologic malignancies in eight cases. Five grafts were fully matched, three were one antigen-mismatched, and two were two antigen-mismatched. Despite GVHD prophylaxis with cyclosporin A and short-term methotrexate, AGVHD occurred after a median of 24 days and clearly progressed under prednisone (median 2 mg/kg), given for a median of 12 days. 25.3 mAb was given at a dosage of 0.1 mg/kg in a 4-h perfusion for five daily doses without any clinical or biological side effects. Thirty percent of the patients experienced a reduction in the overall grading with two complete responses. Partial response in at least one involved organ (mostly skin) occurred in 80% of the patients. However, seven out of the eight responding patients experienced a new episode of AGVHD. This observation, which confirms that inhibiting a functional molecule is as efficient as a cytolytic therapy, offers an alternative strategy to antithymocyte globulin (ATG) and cytotoxic mAb in controlling steroid-resistant GVHD.

Acute Disease↗
PubMed1991

Cell surface expression of ICAM-1 (CD54) and LFA-3 (CD58), two adhesion molecules, is up-regulated on bone marrow leukemic blasts after in vivo administration of high-dose recombinant interleukin-2.

High-dose recombinant interleukin-2 (rIL-2) therapy can induce long-term remission in patients with melanoma and renal and colon cancer. More recently, in vivo IL-2 therapy was shown to induce complete or partial remission in some cases of relapsed chemotherapy-resistant acute myeloid leukemia. We have investigated the phenotypic modifications of bone marrow cells obtained from five patients with acute myeloid leukemia in relapse receiving high-dose i.v. rIL-2. We found that, in three of five patients, IL-2 could induce, in vivo, an increase in the expression of CD54/ICAM-1 and to a lesser extent of CD58/LFA-3 on bone marrow leukemic blasts. This demonstrates that rIL-2 modifies directly or indirectly the expression of the cell surface molecules of the tumor cells themselves. Upregulation of such adhesion molecules could account for the enhancement of cell interactions between the tumor and effector cells such as T, natural killer, and phagocytic cells as well as being indicators of differentiation signaling.

Antigens, CD↗
PubMed1991

Histological evolution of peripheral T-cell lymphomas. Study of six cases.

The authors report 6 cases of histological transformation in peripheral T-cell lymphomas of low grade of malignancy. The transformation occurs in 75% of the cases, in extra-nodal sites and corresponds to a monomorphic of pleiomorphic large cell type. There is no discordance in the immunologic results between the two phases. The transformation seems to occur earlier than in B lymphomas, with a relative frequency of hematological manifestations and no therapeutic response.

Aged↗
PubMed1991

Role of splenectomy in incidence and severity of acute graft-versus-host disease: a multicenter study of 157 patients.

Allogeneic bone marrow transplantation is a therapeutic option for many hematological malignancies. Graft-versus-host disease (GVHD) remains one of the major complications and has a high mortality rate. The pathophysiological mechanisms involved are poorly understood and GVHD prevention regimens still give disappointing results. This study concerned 157 patients with diverse diagnoses from Bordeaux, Grenoble and Marseille who had undergone an HLA-matched transplantation without T cell depletion. Thirty-one patients (20%) had been splenectomized before transplantation. The role of splenectomy in the incidence and severity of acute GVHD was investigated using a univariate and multivariate analysis of 11 risk factors including splenectomy. Univariate analysis found three significant risk factors linked with GVHD incidence: splenectomy, age of recipient and GVHD prevention by monotherapy versus a combination of methotrexate plus cyclosporin. Multivariate analysis retained only the effects of age and GVHD prevention on GVHD incidence and showed that splenectomy was the most important factor in GVHD severity. One explanation for the role of splenectomy could be the spleen's possible function as a filter of activated T lymphocytes from the transplant. We therefore concluded that it would be preferable to abstain from splenectomizing patients before transplantation although splenectomy is still advisable in certain malignancies after transplantation.

Acute Disease↗
PubMed1991

Prevention of acute GVHD by in vivo use of anti-interleukin-2 receptor monoclonal antibody (33B3.1): a feasibility trial in 15 patients.

Results of allogeneic bone marrow transplantation (BMT) are still impaired due mainly to acute graft-versus-host disease (GVHD). Successful T cell depletion may abolish GVHD but causes increased rates of rejection and relapse. In vivo blocking of the CD25 receptor on T cells induces efficient and selective immunosuppression. We present results of a pilot trial studying the use of a CD25 MoAb (33B3.1) to prevent acute GVHD after allogeneic BMT. Fifteen patients were included in the study; 14 had a fully HLA matched sibling donor. In association with short methotrexate and cyclosporin A post-graft immunosuppression, the patients received 10 mg of 33B3.1 monoclonal antibody daily according to three successive schedules to study toxicity on marrow graft. No major adverse clinical experiences occurred. Engraftment was not delayed; after 4 months, full chimerism was documented in 14/15 studied patients. No human anti-rat antibody was detected during treatment period. No GVHD occurred during the period of antibody administration. Two patients relapsed; seven are alive and well with a median follow-up of 650 days. This study justifies a prospective controlled study to determine the real impact of 33B3.1 on GVHD prophylaxis.

Acute Disease↗
PubMed1990

Hematologic and immunologic effects of the systemic administration of recombinant interleukin-2 after autologous bone marrow transplantation.

T cells from allogeneic bone marrow grafts are responsible for a graft versus leukemia effect. Use of recombinant Interleukin-2 (rIL-2) after autologous bone marrow transplantation (BMT) may enhance immune function and hopefully reproduce the allogeneic reaction. We report here the hematologic and immunologic changes observed in the first 10 patients of a phase 1 trial studying the infusion of IL-2 after autologous BMT. All patients had high-risk malignancies and received 6 days of a constant infusion of IL-2 (Eurocetus, Amsterdam, The Netherlands) at dose of 3 x 10(6) Cetus Units/m2/d, 79 +/- 12 days after autologous BMT. Clinical toxicities involving cutaneous, cholestatic, gastrointestinal, and hemodynamic effects occurred during IL-2 treatment but reversed in all cases. Completion of treatment was 91% of the scheduled dose of IL-2. Hematologic toxicity was moderate and transient with no graft failure. Increases in eosinophil and lymphocyte counts were significant (P less than .05). Stimulation of the immune system was intense and prolonged, manifested by increase numbers of CD3+, CD3+DR+, CD3+ CD25+ lymphocytes, and natural killer (NK) cells (all P less than .01), and increase of Lymphokine-activated killers (LAK) and NK activities (P less than .01 and P less than .05). This study establishes the feasibility of a 6-day administration of rIL-2 after autologous BMT leading to a major immune activation 2.5 months after BMT.

Adolescent↗