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M Unterhalt

Publications and source records attributed to M Unterhalt.

18 recordsLinked to original sources
PubMed1996

[Therapy of low-grade non-Hodgkin lymphomas].

Low-grade non-Hodgkin's lymphomas are characterized by a low proliferative activity and prolonged clinical course. Most of them reveal distinct cytogenetic and molecular aberrations, such as the translocation t (14; 18) in centrocytic/centroblastic or follicular lymphomas, which is combined with an overexpression of the bcl 2 oncogene or the translocation t (11; 14), which is associated with a deregulation of the PRAD 1 gene and is mainly found in centrocytic or mantle-cell lymphomas. The therapy of low-grade non-Hodgkin's lymphoma depends on the extent of the disease. In early stages I and II, in which only 15 to 25% of low-grade lymphomas are diagnosed, radiotherapy represents the treatment of choice and may be applied with curative intention. The appropriate treatment of more advanced stages III and IV is a matter of controversial debates. Currently, it still seems justified to watch the natural course of the disease and to start therapy not before the occurrence of B-symptoms, hematopoietic insufficiency or progression of lymphoma. Intensification of initial cytoreductive chemotherapy does not result in a prolonged survival or a higher remission rate. However, maintenance therapy with interferon alpha following successful initial cytoreductive chemotherapy appears to have a favorable impact on disease-free and possibly also overall survival. New perspectives result from the introduction of new cytostatic compounds and the purine analogues in particular as well as the development of effective immunotoxins and antibody-conjugated radio-isotoes. Furthermore, myeloablative radiochemotherapy followed by autologous bone marrow or peripheral stem cell transplantation provides a promising approach with curative potential even in advanced stages of the disease.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Oral idarubicin pharmacokinetics--correlation of trough level with idarubicin area under curve.

Idarubicin is the first anthracycline that can be successfully administered via the oral route and thus may facilitate antineoplastic chemotherapy at an improved quality of life. These perspectives are somewhat hampered by the large variation in bioavailability between individual patients and the obvious requirement to monitor plasma concentration and area-under the curve values (AUC) for an appropriate adjustment of idarubicin dose. In this study we describe the pharmacokinetics of idarubicin and its main metabolite idarubicin in 12 patients after oral application of 20 mg/m2 idarubicin on 3 consecutive days and demonstrate that the 24-h trough levels shows high correlation with AUC and may thus allow a rapid and easy determination of individual drug concentrations and an appropriate dose adjustment. The average terminal half-life was 30.5h for idarubicin and 66.9 h for idarubicinol. The AUC for idarubicin and its main metabolite idarubicinol revealed a substantial interpatient variation with AUC values ranging from 25.7 to 114 ng x h/ml (average 58.1 ng x h/ml) for idarubicin and from 109.4 - 445.2 ng x h/ml (average 287.3 ng x h/ml) for idarubicinol. However, the ratio of idarubicin/idarubicinol differed only two-fold from 1:3.7 to 1:7.7 with an average of 1:5.1. Both idarubicin and idarubicinol concentrations were highly reproducible, however, upon measurements after repeated applications within individual patients. Moreover, idarubicinol and idarubicin AUCs showed a good correlation with r=0.78, indicating that the interindividual variations of idarubicin AUC reflects differences in absorptions rather than metabolism. In order to describe the interindividual bioavailability of idarubicin - represented by AUC - measurement of a single data point with a high correlation with the AUC would be ideal. Our study demonstrates that the 24-h trough level shows such an excellent correlation (r=0.96) with AUC, making it the perfect candidate for fast estimates of the individual bioavailability in a given patient. On this basis, the longitudinal measurement of the 24-h trough level may allow the assessment of the impact of interindividual variations in AUC of clinical outcome and toxicity.

Acute Disease↗
PubMed1996

Prednimustine, mitoxantrone (PmM) vs cyclophosphamide, vincristine, prednisone (COP) for the treatment of advanced low-grade non-Hodgkin's lymphoma. German Low-Grade Lymphoma Study Group.

The current study was initiated to compare the anti-lymphoma activity and side-effects of prednimustine/mitoxantrone (PmM) vs cyclophosphamide, vincristine, prednisone (COP) in patients with advanced low-grade non-Hodgkin's lymphomas in way of a prospective randomized multicenter trial. Two hundred and forty-six patients with stage III or IV centroblastic-centrocytic (CB-CC (Kiel-classification)) or follicle center lymphoma (FCL (REAL classification)) and centrocytic (CC) or mantle-cell-lymphoma (MCL) were randomized for therapy with either PmM or COP and are fully evaluable for response and toxicity. PmM consisted of prednimustine 100 mg/m2/day on days 1-5 and mitoxantrone 8 mg/m2 /day days 1 and 2, while COP comprised cyclophosphamide 400 mg/m2/day on days 1-5, vincristine 1.4 mg/m2/day on day 1 and prednisone 100 mg/m2/day on days 1-5. Both regimens were repeated for a total of six cycles followed by an additional two courses for consolidation in responding cases and a subsequent second randomization for interferon alpha maintenance vs observation only. Overall response rates were comparable with 83% complete and partial remissions after COP and 84% remissions after PmM. PmM revealed a significantly higher rate of complete remissions (36 vs 18%, P < 0.006), the majority being achieved after four courses. The more rapid and possibly also more effective reduction of the lymphoma cell mass by PmM resulted in a tendency to a longer event-free interval for patients achieving remissions after PmM as compared to COP with estimated median event-free intervals of 31 vs 14 months, respectively (P=0.04). Separate analysis of lymphoma subtypes showed a tendency to a lower rate of complete remission in CC or MCL as compared to CB-CC or FCL (16 vs 30%, P=0.12, NS) while overall response rates were in a similar range (81 vs 85%). In both subtypes, PmM induced a higher rate of complete remission while overall response rates were comparable after PmM or COP. Treatment associated side-effects comprised predominantly myelosuppression and granulocytopenia in particular which was more frequently observed after PmM than COP (43 vs 31 %, P < 0.0001). This difference was clinically irrelevant, however, since serious infectious complications were encountered in less than 3% of cycles after both regimens. COP therapy was associated with a significantly higher incidence and degree of hair loss and complete alopecia (31 vs 2%) as well as of peripheral neurotoxicity (23 vs 2%). These data show that both PmM and COP reveal a high anti-lymphoma activity in patients with advanced stage non-Hodgkin's lymphoma. PmM appears advantageous with a higher rate of complete remissions and a better tolerability with regard to secondary side-effects. A longer follow-up is needed to assess the long-term effects of initial treatment on disease-free and overall survival and the impact on additional maintenance therapy with interferon alpha.

Adult↗
PubMed1996

De novo AML with dysplastic hematopoiesis: cytogenetic and prognostic significance.

Dysplastic hematopoiesis is the morphological hallmark of myelodysplastic syndromes. Dysplastic features in one or more lineages are also found frequently in bone marrow aspirates from patients with de novo AML and have been associated with an unfavorable prognosis. We asked whether dyshematopoiesis is an independent prognostic factor or an indicator of unrecognized secondary leukemia, identified by characteristic chromosomal abnormalities. Bone marrow aspirates from 102 patients with newly diagnosed AML were analyzed. Morphological analysis was obtained in all patients, flow cytometric analysis in 96 and successful cytogenetic analysis in 65 bone marrow aspirates. Dysgranulopoiesis (DysG) was found in 55, dysmegakaryopoiesis (DysM) in 32 and dyserythropoiesis (DysE) in 23 patients. Decreased side scatter signals of neutrophils in the flow cytometric analysis (DysS) were detected in 32 patients. DysG and DysS showed a highly significant correlation (P = 0.0005). DysG was an adverse negative prognostic factor for remission rate and event-free survival (P = 0.04, P = 0.02). An unfavorable karyotype was associated with a significantly lower chance for event-free survival (P = 0.002). The incidence of an unfavorable karyotype was significantly higher in patients with DysG (P = 0.01), DysM (P = 0.02) and DysS (P = 0.01). In patients with an unfavorable karyotype, dysplasia had no additional prognostic influence, however, in patients with a normal, favorable or prognostically uncertain karyotype DysG remained a predictor of lower remission rate (P = 0.03). We conclude that dysgranulopoiesis, dysmegakaryopoiesis and decreased side scatter signals of neutrophils are indicators of secondary leukemias in bone marrow aspirates from patients with de novo AML.

Bone Marrow↗
PubMed1995

Highly sensitive coupled-column high-performance liquid chromatographic method for the separation and quantitation of the diastereomers of leucovorin and 5-methyltetrahydrofolate in serum and urine.

A column-switching chiral HPLC assay was developed that allows the separation and quantitation of the diastereomers of leucovorin (LV, 5-formyltetrahydrofolic acid) and its metabolite 5-methyltetrahydrofolate (METHF) in serum and urine by means of fluorescence detection. The analysis procedure consists of an on-line concentration of the folates in the HPLC system which is followed by the elution and separation of folates on an achiral 3-microns Microbore C18 column in (6R,S)-LV and (6R,S)-METHF. (6R,S)-LV and (6R,S)-METHF are subsequently transferred on-line onto a chiral 7-microns bovine serum albumin column through a Rheodyne valve system and are separated into their diastereometers. Time of analysis is 70 min. Detection limit is 5 ng/ml for each diastereometer. The within-day variation ranges between 3.2 and 15.8% in relation to the measured concentration. Between-day variation is 4.4-12.1% for a concentration of 100 ng/ml for each diastereometer. (6R,S)-LV and (6S)-LV pharmacokinetics were assessed by analyzing serum and urine samples of four-healthy volunteers.

Antineoplastic Agents↗
PubMed1995

Highly sensitive high-performance liquid chromatographic assay for 1-beta-D-arabinofuranosylcytosine-5'-stearyl phosphate (cytarabine-ocfosfate).

An ion-pair HPLC method for the determination of 1-beta-D-arabinofuranosylcytosine-5'-stearyl phosphate (cytarabine-ocfosfate I) was developed, using a phenyl-bonded column under reversed-phase conditions with a mobile phase of acetonitrile-buffered water (pH 6.8) (50:50) for isocratic elution. A reproducible sample clean-up was achieved by solid-phase extraction. In order to reach the low limit of detection of 2 ng/ml, an enrichment switching system was used. The present validation leads to a limit of quantification of 5 ng/ml with a coefficient of variation (C.V.) of 10%. The total time of measurement was shortened by a back-flush procedure to restore the conditions after each run. UV detection at 275 nm was applied. The recoveries for plasma samples ranged from 56.4 to 64.1%, regardless of drug concentrations. The intra-assay C.V. was about 4% (40 measurements at four different concentrations). The inter-assay recovery (ten measurements over ten days) at a plasma concentration of 50 ng/ml was 57% with a C.V. of 8.25%. Based on this HPLC method, the pharmacokinetics of I were measured during a clinical phase I/II study.

Antineoplastic Agents↗
PubMed1995

Blast cell proliferative activity and sensitivity to GM-CSF in vitro are associated with early response to TAD-9 induction therapy in acute myeloid leukemia.

The current study was undertaken to determine the relevance of leukemic blast cell proliferative activity, cellular parameters of Ara-C metabolism and the in vitro sensitivity to GM-CSF in association with the clinical response to TAD-9 induction therapy in 66 patients with de novo acute myeloid leukemia (AML). Proliferative activity was assessed by 3H-thymidine (3H-TdR) incorporation and thymidine kinase (TK) activity, parameters of Ara-C metabolism comprised the activities of deoxycytidine kinase (DCK) and DNA polymerase alpha (poly alpha) as well as Ara-CTP concentrations and 3H-Ara-C uptake into DNA. GM-CSF sensitivity was determined by in vitro incubation of blasts for 48 h with or without GM-CSF (100 U/ml) followed by an additional 4 h concurrent exposure to GM-CSF and 3H-TdR (0.5 microCi/ml). The following results were obtained as expressed by median values and ranges: 3H-TdR incorporation: 1.07 pmol/10(5) cells (0.0-10.1), TK: 7.3 pmol/min/mg protein (1.3-56.0), DCK: 9.3 pmol/min/mg protein (0.77-47.1), poly alpha: 1.7 pmol/min/mg protein (0.00-28.9), Ara-CTP: 53.3 ng/10(7) cells (13.3-211.0), 3H-Ara-C uptake: 0.06 pmol/10(5) cells (0.0-0.57). 3H-Ara-C uptake was correlated with 3H-TdR incorporation (r = 0.74) and with the (S-phase dependent) activities of TK (r = 0.73) and poly alpha (r = 0.71, but not with DCK activity or intracellular Ara-CTP content. Blast cells of 37 from 55 analyzed patients were found to be sensitive to GM-CSF stimulation as defined by an increase in 3H-TdR incorporation > or = 1.5-fold over control values after the 48 h GM-CSF exposure. In vitro data were related with clinical response to TAD-9 induction therapy in 43 patients with newly diagnosed AML, taking the blast cell reduction at day 10 or 16 to < 5% or > or = 5% residual blasts as early parameter for adequate or inadequate response, respectively. While neither 3H-Ara-C uptake, nor intracellular Ara-CTP concentration, TK nor DCK activity were predictive for response, a high 3H-TdR incorporation and a high poly alpha activity were associated with adequate blast cell reduction. Median values of 3H-TdR incorporation were 2.26 pmol/10(5) cells for patients with adequate blast cell clearance and 0.80 pmol/10(5) cells for patients with inadequate blast cell clearance (P = 0.11), the respective values for poly alpha were 3.22 pmol/min/mg protein for responders and 1.1 pmol/min/mg protein for non-responders (P = 0.0085).(ABSTRACT TRUNCATED AT 400 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Pharmacokinetics of Ara-CMP-Stearate (YNK01): phase I study of the oral Ara-C derivative.

Ara-CMP-Stearate (1-beta-D-arabinofuranosylcytosine-5'-stearylphosphate, YNK 01, Fosteabine) is the orally applicable prodrug of cytosine-arabinoside (Ara-C). During a phase I study in patients with advanced low-grade non-Hodgkin lymphomas or acute myeloid leukemia, the pharmacokinetic parameters of Ara-CMP-Stearate (kindly provided by ASTA Medica, Frankfurt, Germany) were determined by HPLC analysis. Seventy-two hours after a first starting dose which served for the determination of baseline pharmacokinetic parameters, Ara-CMP-Stearate was administered over 14 days by daily oral application. Ara-CMP-Stearate was started at a dose of 100 mg/day and was escalated in subsequent patients to 200 mg/day and 300 mg/day. Plasma and urine concentrations of Ara-CMP-Stearate, Ara-C and Ara-U were measured during the initial treatment phase and within 72 h after the end of the 14-day treatment cycle. So far six patients have been treated with 100 mg/day, three with 200 mg/day and another six with 300 mg/day. One patient was treated consecutively with 100 mg, 300 mg and 600 mg. Fitting the results of the plasma concentration measurements of Ara-CMP-Stearate to a one-compartment model, the following pharmacokinetic parameters were obtained (average and variation coefficient VC). Ara-CMP-Stearate dose-independent parameters: lag time = 1.04 h (0.57); tmax = 5.72 h (0.30); t1/2 = 9.4 h (0.36). Dose-dependent parameters: at 100 mg: AUC = 1099 ng/h/ml (0.31); concentration(max) = 53.8 ng/ml (0.28); at 200 mg: AUC = 2753 ng/h/ml (0.32); concentration(max) = 154.8 ng/ml (0.46); at 300 mg: AUC = 2940 ng/h/ml (0.66); concentration(max) = 160.0 ng/ml (0.59). The long lag time and late tmax can be explained by resorption in the distal part of the small intestine. No Ara-CMP-Stearate was detected in urine samples (limit of detection = 500 pg/ml). Pharmacokinetic parameters of Ara-C following Ara-CMP-Stearate application showed the following characteristics: t1/2 = 24.3 h (0.39); AUC (100 mg) = 262 ng/h/ml (0.93); AUC (200 mg) = 502 ng/h/ml (0.87); AUC (300 mg) = 898 ng/h/ml (1.07). Since Ara-CMP-Stearate causes intravascular hemolysis after intravenous administration, it was not possible to determine its bioavailability by comparing the AUC after oral and i.v. application. Instead, the renal elimination of Ara-U, as the main metabolite of Ara-C was measured during the first 72-h period and after the last application.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
PubMed1994

Current status and future perspectives in the treatment of low-grade non-Hodgkin's lymphomas.

Low-grade non-Hodgkin lymphomas (NHL) comprise a heterogeneous group of disorders both in terms of their cellular and histological composition as well as in terms of their clinical course. The most usually applied classification systems, the Working Formulation and the Kiel classification as well as the recently proposed Revised European American Lymphoma classification, discriminate between low-, intermediate- and high-grade subtypes. In general, low-grade NHL are characterized by a low to moderate proliferative activity and a long clinical course with median survival times ranging from approximately 3 years for centrocytic (CC) or mantle-cell lymphomas (MCL) to 5-8 years for centroblastic-centrocytic (CB-CC) or follicular lymphomas (FL). Recent cytogenetic and molecular biologic analyses indicate that these differences may result from distinct genetic abnormalities such as the translocation t(14;18), which is frequently observed in FL-NHL and is associated with a bcl-2 overexpression and inhibition of apoptosis, or the deregulation of PRAD1 in MCL-NHL induced by the translocation t(11;14). Therapy of low-grade lymphomas depends mainly on the extent of the disease. In the early stages I and II, at which approximately 15 to 20% of low-grade NHL are diagnosed, radiotherapy may be applied with curative intention. The treatment of patients with more advanced stages III and IV is controversial. The currently available information justifies a conservative approach of observing the natural course of the disease until therapeutic intervention is required due to the occurrence of B-symptoms, hematopoietic insufficiency or lymphoma progression.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

New aspects on the pharmacokinetics of mitoxantrone and its two major metabolites.

In spite of its broad clinical application in the treatment of malignant disorders, the pharmacokinetics of mitoxantrone are still not fully understood and warrant further investigation. Information is also limited about interindividual differences in the plasma AUC infinity (area-under-the-curve concentration to time infinity) and renal elimination of mitoxantrone and its main metabolites, mono- and dicarboxylic acid. In the present study, the plasma concentration of mitoxantrone was measured by HPLC during 120 h after the end of a 30-min infusion of 10 mg/m2 in 18 patients undergoing combination therapy with mitoxantrone and high-dose cytosine arabinoside for acute myeloid leukemia. Plasma kinetics and renal elimination of mono- and dicarboxylic acid were analyzed in addition in eight of these patients, and in five cases with chronic lymphocytic leukemia receiving a 30-min infusion of 5 mg/m2 mitoxantrone weekly for 3 consecutive weeks. Fitting the results to a three compartment model, a substantial interindividual variation was observed for plasma and urine pharmacokinetics. Plasma AUC infinity for mitoxantrone differed approximately 13-fold between individual patients and varied between 80-1030 ngh/ml. The corresponding values for mono- and dicarboxylic acid ranged from 23-147 ngh/ml and 51-471 ngh/ml, respectively. The median terminal half-life for mitoxantrone was similar to that of the mono- and dicarboxylic acid and was 75 h. Cumulative renal elimination ranged from 670-1950 micrograms for mitoxantrone, from 366-852 micrograms for monocarboxylic acid, and from 792-3420 micrograms for dicarboxylic acid. Renal clearance of mitoxantrone reached a median level of 69 ml/min and for the total plasma clearance a median of 1136 ml/min was found. The corresponding values for the mono- and dicarboxymetabolites were 57 and 67 ml/min. In contrast to the great interindividual differences in pharmacokinetic results, a low intraindividual variability was observed upon repeated determinations of renal elimination of mitoxantrone and its metabolites at weekly intervals in five patients. These data provide new insights into the pharmacokinetic of mitoxantrone and its main metabolites revealing substantial differences in drug metabolism and elimination between individual patients. Further studies are needed to explore the potential impact on response and/or toxicity and the requirement of a pharmacokinetic directed adjustment of drug dosage in clinical trials.

Acute Disease↗
PubMed1993

Column-switching solid-phase trace-enrichment high-performance liquid chromatographic method for measurement of buprenorphine and norbuprenorphine in human plasma and urine by electrochemical detection.

We describe a new high-performance liquid chromatographic method using electrochemical detection for the determination of buprenorphine and norbuprenorphine in plasma and urine. The minimum concentration for detection of buprenorphine and norbuprenorphine is 40 pg/ml. The intra-assay coefficient of variation (C.V.) in plasma and urine samples ranges from 6 to 17% depending on the drug concentration. At a plasma concentration of 500 pg/ml the inter-assay C.V. is 8% for buprenorphine and 9% for norbuprenorphine. The analysis duration is 16 min. After solid-phase extraction and evaporation a valve-switching system with two Rheodyne valves enables sample enrichment, optimal sample cleaning and rapid elution of long-retained substances.

Buprenorphine↗
PubMed1993

Fludarabine single-agent therapy for relapsed low-grade non-Hodgkin's lymphomas: a phase II study of the German Low-Grade Non-Hodgkin's Lymphoma Study Group.

In a phase II study, 45 patients with advanced low-grade non-Hodgkin's lymphomas (NHLs) who had failed on or had relapsed after first-line chemotherapy were treated with a 5-day regimen of fludarabine, 25 mg/m2/d, by a 30-minute infusion. All patients were pretreated and had received one to 11 preceding regimens (median, three regimens). Histologic subtypes included 17 centrocytic/centroblastic NHLs, three centrocytic NHLs, 23 lymphoplasmocytoid immunocytomas, and one case each of peripheral T-cell and lymphocytic lymphoma. From 38 presently evaluable patients, 12 (31%) cases responded (five [13%] complete and seven [18%] partial remissions). Treatment-associated toxicity was mild to moderate, with myelosuppression comprising the major side effect. From the 12 complete and partial response patients, seven are currently in unmaintained remission for more than 12 months. These data indicate a high activity of fludarabine in heavily pretreated patients with low-grade NHL. Further investigations are warranted to assess the most appropriate usage for this highly promising agent at earlier stages of low-grade NHL therapy.

Adult↗
PubMed1992

Flow cytometric characterization of acute myeloid leukemia: IV. Comparison to the differentiation pathway of normal hematopoietic progenitor cells.

Gradual increase of CD38 on cells expressing CD34 characterizes the early cell differentiation pathway of normal human hematopoietic progenitors. In this study the coordinated expression pattern of CD34 and CD38 was assessed on leukemic blasts from bone marrow aspirates of 95 patients with newly diagnosed acute myeloid leukemia (AML). Expression was divided into six categories analogous to the differentiation pathway of normal bone marrow. The CD38 antigen was expressed on the leukemic cells of all patients and CD34+ leukemic cells were found in 79 patients (83%). In 93 patients, the leukemic cells were found along the differentiation pathway defined by CD34 and CD38. In 33 of the 93 patients, a part of the CD34+ cells did not express the CD38 antigen (categories 1 and 2). In another 33 patients, all CD34+ cells expressed CD38 (categories 3 and 4). In the remaining 27 patients, only cells were found which dimly expressed CD34 or did not express CD34 (categories 5 and 6). Of the 93 patients, 88 were treated with intensive chemotherapy according to the protocol of the German AML Cooperative Group. Of these, 21 died early and were not evaluable for treatment response. Complete remission was achieved in 14 of 22 patients (64%) in categories 1 and 2, in 19 of 26 patients (73%) in categories 3 and 4, and in 18 of 19 patients (95%) in categories 5 and 6. The event-free survival was significantly longer in patients of categories 5 and 6 compared to patients in categories 1 and 2 (p less than 0.01) and categories 3 and 4 (p less than 0.05), respectively. We conclude that in the majority of AML patients the immunophenotype of leukemic cells follows the early cell differentiation pathways defined by coordinated expression of CD34 and CD38 similar to that of normal hematopoietic progenitors. The presence of cells in the late cell differentiation stages (CD34+/-, CD38 /+) identifies patients with a higher complete remission rate and longer complete remission duration.

ADP-ribosyl Cyclase↗
PubMed1992

Differences in the intracellular pharmacokinetics of cytosine arabinoside (AraC) between circulating leukemic blasts and normal mononuclear blood cells.

The increasing insights into the pharmacokinetics and the metabolism of cytosine arabinoside (AraC) have improved the rationale for its application in leukemia therapy and have led to a pharmacologically directed design of antileukemic treatment. The current study aims at adding to this approach by detecting differences in the intracellular metabolism of AraC 5'-triphosphate (AraCTP) between leukemic and normal mononuclear blood cells. Measurements of intracellular AraCTP levels were complemented by determinations of plasma AraC and AraU concentrations and were performed in 32 patients with acute myeloid leukemia undergoing combination therapy including either conventional (100 mg/m2 daily) or high-dose (1.0 or 3.0 g/m2 twice daily) AraC. Plasma AraC concentration showed a linear relationship to the applied AraC dose but did not correlate with intracellular AraCTP levels. During conventional-dose AraC therapy little interpatient variation was observed in AraCTP retention times in leukemic blasts from 5 patients with t1/2 values ranging from 1.70 to 2.50 h (median 2.14 h). In all cases AraCTP levels declined rapidly after the end of the AraC infusion. Substantial differences in AraCTP retention times were revealed, however, during 3 h infusions of either 1.0 or 3.0 g/m2 AraC in leukemic blasts from 10 patients with t1/2 values between 1.60 to 7.63 h (median 2.42 h). In addition, AraCTP levels declined in only one patient by > 10% within the first hour after the end of therapy and remained constant or even increased up to 1.5-fold in a post-treatment period of 1 to 2.5 h in the other nine cases. In contrast, AraCTP retention times were relatively uniform in normal mononuclear blood cells from 11 patients with t1/2 values of 3.34 to 5.29 h (median 3.85 h). More importantly, AraCTP levels dropped by > 10% within the first hour after the end of the high-dose AraC infusion in eight of 11 cases. A post-therapeutic increase > 10% was not observed in any patient. Similar findings emerged after in vitro exposure of normal bone marrow cells from six healthy volunteers to 20 mumol/l AraC for 3 h revealing a > 10% decrease of intracellular AraCTP within the first post-treatment hour in all cases with AraCTP retention times of 2.29 to 8.63 h (median 3.20 h). These differences in AraCTP pharmacokinetics between leukemic and normal blood cells may provide the basis for a modified timing of AraC administration with the aim of selectively maintaining cytotoxic AraCTP levels in leukemic blasts while allowing an intermittent drop of AraCTP levels in normal cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Acute Disease↗
PubMed1991

alpha Interferon maintenance therapy in patients with low-grade non-Hodgkin's lymphomas after cytoreductive chemotherapy with prednimustine and mitoxantrone.

A combination of prednimustine 100 mg/m2/day orally, days 1-5, and mitoxantrone 8 mg/m2/day intravenously, days 1 and 2, was administered to 19 patients with advanced low-grade non-Hodgkin's lymphoma after failure on or relapse after standard chemotherapy. The prednimustine and mitoxantrone (PmM) regimen was repeated every 4-6 weeks to a maximum of six cycles. Thirteen patients, achieving a complete (4) or partial (9) remission (CR or PR), received two additional courses for consolidation followed by interferon alfa-2b 5 million units (MU) subcutaneously (s.c.) three times weekly until progression or relapse. At the present time, remission duration ranges from 4.5+ to 17.5+ months, with a median of 14.5 months. In a historical comparison to unmaintained first remission preceding the PmM/interferon trial, a tendency towards a longer period of freedom from progression was apparent in the 13 patients receiving interferon maintenance treatment during their second PR or CR. These data provided the basis for a currently ongoing multicentre study randomly comparing initial chemotherapy with PmM versus cyclophosphamide/vincristine (Oncovin)/prednisone (COP) in patients with advanced centroblastic-centrocytic and centrocytic non-Hodgkin's lymphomas, followed by a second randomization in CR and PR patients for maintenance with alpha interferon versus observation only.

Adult↗
PubMed1990

Treatment of low-grade non-Hodgkin's lymphoma by cytoreductive chemotherapy with prednimustine/mitoxantrone followed by interferon alpha-2b maintenance: results of a clinical phase II study.

In a clinical phase II study, the antitumor activity of the recently introduced combination of prednimustine and mitoxantrone (PmM) was evaluated in 17 patients with advanced low-grade non-Hodgkin's lymphoma after failure with or relapse after standard chemotherapy. The PmM regimen consisted of prednimustine 100 mg/m2/d orally on days 1 to 5, and mitoxantrone 8 mg/m2/d intravenously on days 1 and 2, giving a total dose of 16 mg/m2. Treatment was repeated every 4 to 6 weeks to a maximum of 6 cycles. Patients achieving complete remission (CR) or partial remission (PR) received two additional courses for consolidation, followed by interferon (IFN) alpha-2b 5 x 10(6) U subcutaneously three times a week until progression or relapse. Twelve of the 17 patients (71%) responded (CR, 4 and PR, 8). Side effects consisted mainly of neutropenia, which required dose reduction in 48% of treatment cycles. All 12 responders subsequently received IFN alpha-2b maintenance treatment. At present, remission duration ranges from 4.5+ to 17.5+ months (median 14.5 months). In comparison to unmaintained first remission prior to receiving PmM/IFN alpha-2b, a clear tendency towards a longer period of freedom from progression emerged in the 12 patients receiving IFN alpha-2b maintenance treatment during a second PR or CR. These data indicate a high antitumor activity of PmM in low-grade non-Hodgkin's lymphoma and suggest a beneficial effect of IFN alpha-2b maintenance. Present findings, however, will require confirmation in future investigations.

Adult↗