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M Unterhalt

Publications and source records attributed to M Unterhalt.

At least 19 recordsLinked to original sources
PubMed2006

Initial chemotherapy with mitoxantrone, chlorambucil, prednisone impairs the collection of stem cells in patients with indolent lymphomas--results of a randomized comparison by the German Low-Grade Lymphoma Study Group.

Myeloablative radio-chemotherapy with subsequent autologous stem cell transplantation (ASCT) significantly prolongs progression free and probably overall survival in follicular lymphoma (FL) in first remission. The current trial explored prospectively the rate of successful stem cell mobilization in patients with advanced stage FL after initial therapy with either Mitoxantrone, Chlorambucil, Prednisone (MCP) or Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP) as part of a prospective randomized comparison of both regimens. ASCT patients received Dexa-BEAM (Dexamethasone, BCNU, Melphalan, Etoposide, Cytarabine) for mobilization of stem cells. Stem cells were collected and a minimum of 2x2.0x106/kg bw CD34+ was required for ASCT. Of 79 evaluable patients, 58 (73%) had follicular lymphoma, 13 (16%) mantle cell lymphoma and 8 (10%) lymphoplasmacytic lymphoma. In the 45 patients assigned to CHOP, stem cell collection was successful in 42 cases (93%, 95% CI 82% to 99%). This high mobilization rate after CHOP could be confirmed in 61 subsequent patients (87%). In contrast, after MCP therapy stem cell collection was successful in only 15 of 34 patients (44%, 95% CI 27% to 62%; P=0.0003). In conclusion, initial therapy with MCP significantly impairs the ability to collect stem cells and should be avoided for first line therapy of younger patients potentially qualifying for high dose consolidation and ASCT in first remission.

Adult↗
PubMed2005

Meta-analysis to evaluate the role of interferon in follicular lymphoma.

PURPOSE: To determine whether interferon (IFN) -alpha2, when given with or following chemotherapy, influences response rate, remission duration, and survival in newly diagnosed patients with follicular lymphoma. PATIENTS AND METHODS: Ten phase III studies evaluating the role of IFN-alpha2 in 1,922 newly diagnosed patients with follicular lymphoma were analyzed. Updated individual patient data were used to perform meta-analyses for response, survival, and remission duration. RESULTS: The addition of IFN-alpha2 to initial chemotherapy did not significantly influence response rate. An overall meta-analysis for survival showed a significant difference in favor of IFN-alpha2, but also showed significant heterogeneity between studies. Further analyses were carried out in order to explain this heterogeneity, and to define the circumstances in which IFN-alpha2 prolonged survival. The survival advantage was seen when IFN-alpha2 was given: (1) in conjunction with relatively intensive initial chemotherapy (2P = .00005), (2) at a dose >/= 5 million units (2P = .000002), (3) at a cumulative dose >/= 36 million units per month (2P = .000008), and (4) with chemotherapy rather than as maintenance therapy (P = .004). With regard to remission duration, there was also a significant difference in favor of IFN-alpha2, irrespective of the intensity of chemotherapy used, IFN dose, or whether IFN was given as a maintenance strategy or with chemotherapy. CONCLUSION: When given in the context of relatively intensive initial chemotherapy, and at a dose >/= 5 million units (>/= 36 x 10(6) units per month), IFN-alpha2 prolongs survival and remission duration in patients with follicular lymphoma.

Adolescent↗
PubMed2004

[Current strategies in the treatment of advanced stage mantle cell lymphoma].

Advanced stage mantle cell lymphoma (MCL) with a median survival of only three years and virtually no long-term survivors represents the lymphoma subtype with the poorest prognosis and remains incurable with conventional chemotherapy. Recently two randomized trials of the German Low Grade Lymphoma Study Group (GLSG) demonstrated the superiority of a combined immunochemotherapy with the anti-CD20 antibody rituximab in first-line therapy (R-CHOP) as well as in relapsed disease (R-FCM). In addition, in a trial of the European MCL Network, intensified-consolidation with high-dose radiochemotherapy followed by autologous stem cell transplantation significantly improved the progression-free survival in patients up to 65 years of age. However, the vast majority of patients with MCL will eventually relapse. Thus, new strategies such as allogenic transplantation after dose-reduced conditioning or novel molecular targeting agents (e. g. proteasome inhibitors or radiolabeled antibodies) are urgently warranted to further improve the long-term outcome of MCL.

Age Factors↗
PubMed2004

[Monoclonal antibody treatment of malignant lymphoma].

In the last years monoclonal antibodies directed against B-cell associated epitopes have enriched our armentarium of therapeutic strategies against malignant B-cell lymphoma. Monoclonal antibodies are characterized by a different mode of action compared to chemotherapy, thereby opening new avenues in lymphoma treatment. These monoclonal antibodies can exert their anti-lymphoma activity directly by an intrinsic cytotoxic effect or indirectly as a carrier of cytotoxic drugs or radioisotopes. Rituximab, an anti-CD20 monoclonal antibody, was proven to be highly active in indolent as well as aggressive lymphoma, in particular when combined with chemotherapy. The anti-CD52 antibody alemtuzumab was shown to induce remissions in high risk CLL. Furthermore, clinical trials have demonstrated promising activity of monoclonal antibodies conjugated to radioisotopes such as the (131)iodine anti-CD20 antibody tositumomab or the (90)yttrium anti-CD20 antibody ibritumomab tiuxetan.

Alemtuzumab↗
PubMed2004

Modern diagnostics in chronic myeloproliferative diseases (CMPDs).

According to the new WHO classification a group of chronic myeloproliferative diseases (CMPDs) were defined: chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia and hypereosinophilic syndrome (CEL/HES), polycythemia vera (PV), chronic idiopathic myelofibrosis (with extramedullary hematopoiesis, CIMF), essential thrombocythemia (ET), and so called CMPD/unclassifiable. As clinical features and laboratory findings differ widely between these diseases several diagnostic approaches are mandatory at diagnosis for classification and are needed also for follow up studies, especially for the measurement of minimal residual disease (MRD). We here outline the laboratory set up at diagnosis and during follow up in CMPDs with specific focus on the respective therapeutical consequences. Only by using a comprehensive diagnostic panel including cytomorphology, cytogenetics, and molecular genetic methods establishing the correct diagnosis, optimizing treatment as well as evaluating treatment response is possible in CMPDs today.

Blood Cell Count↗
PubMed2002

[Increased response rate with rituximab in relapsed and refractory follicular and mantle cell lymphomas -- results of a prospective randomized study of the German Low-Grade Lymphoma Study Group].

BACKGROUND AND OBJECTIVE: Rituximab has shown a high activity in relapsed follicular lymphomas when given alone. Further on, phase-II-studies indicate that its addition to chemotherapy may improve the response rate substantially. However, so far, prospective randomized studies have not been available. PATIENTS AND METHODS: In 1998 the GLSG started a multicenter trial in patients with relapsed or refractory indolent lymphoma or mantle cell lymphoma. A fludarabine-containing regimen (FCM) was chosen for salvage therapy, with fludarabine 25 mg/m(2)/d 1-3, cyclophosphamide 200 mg/m(2) d 1-3 and mitoxantrone 8 mg/m(2) d 1. A total of four courses, every 4 weeks were given. Patients were prospectively randomized for FCM alone or the immunochemotherapy with R-FCM (375 mg/m(2) one day before FCM) RESULTS: About 147 randomized patients 93 had follicular, 40 mantle cell and 14 lymphoplasmocytic/-cytoid lymphoma. Statistical analysis was performed by sequential testing and indicated for 94 fully evaluable patients a significant advantage for the R-FCM-arm, with an overall response rate of 83 % as compared to 58%, when treated with FCM alone (CR: 35 % vs. 13 %). Similar improvements of remission rate were detected in the different lymphoma subgroups, especially in MCL (OR: 65 % vs. 33 %). Both treatment options were associated with hematological toxicities of grade III and IV, but well tolerated; infectious complications were rare, with no difference between the two treatment groups. CONCLUSION: This prospectively randomized trial demonstrates for the first time a significant improvement of the combined immunochemotherapy related to the remission rate in patients with relapsed or refractory indolent lymphoma.

Adult↗
PubMed2001

Efficacy of fludarabine, intermittent sequential high-dose cytosine arabinoside, and mitoxantrone (FIS-HAM) salvage therapy in highly resistant acute leukemias.

Patients with refractory acute leukemias after intensive induction and salvage attempts have a particularly poor prognosis and therapeutic options are limited. In the current study, the pharmacologically based FIS-HAM regimen was applied, which included fludarabine 15 mg/m2 q 12 h (days 1, 2, 8, and 9), cytosine arabinoside as a 45-min infusion every 3 h at 750 mg/m2 per single application (days 1, 2, 8, and 9), and mitoxantrone 10 mg/m2 (days 3, 4, 10, 11). Twenty-six intensively pretreated patients [median age: 38 years; range: 22-65; 16 cases of acute myeloid leukemia (AML) and 10 of acute lymphoblastic leukemia (ALL)] were included. Of 16 patients with AML, 5 achieved a complete remission (CR, 31%), 1 a partial remission (PR, 6%), 2 were nonresponders (13%), and 8 succumbed to early death (ED, 50%). Of 10 patients with ALL, 5 achieved a CR, 1 a PR, 1 was a nonresponder, and 3 died early. Overall, the CR rate was 38%. The median disease-free survival time was 50 days and median survival 90 days. Two patients underwent allogeneic bone marrow transplantation and are alive after 27 and 28 months. Neutropenia amounted to a median of 46 days. Toxicity WHO III/IV included infection (61%), diarrhea (48%), nausea/vomiting (43%), impairment of heart function (30%), and mucositis (26%). The current data indicate a significant activity of FIS-HAM chemotherapy in advanced acute leukemias. However, due to its pronounced toxicity, this regimen should be restricted to third-line therapy for patients expecting a suitable donor for allogeneic transplantation, and supportive treatment should be optimized.

Acute Disease↗
PubMed2000

IDEC-C2B8 (Rituximab) anti-CD20 antibody treatment in relapsed advanced-stage follicular lymphomas: results of a phase-II study of the German Low-Grade Lymphoma Study Group.

PURPOSE: The current study was initiated to assess the clinical efficacy and side effects of rituximab in patients with relapsed advanced stage follicular lymphoma. PATIENTS AND METHODS: The study was performed as an open-label non-randomized multicenter phase-II trial and included patients older than 18 years of age with relapsed advanced-stage follicular lymphomas (FL) grades I and II, according to the REAL classification, or with centroblastic/centrocytic (CB/CC lymphomas according to the Kiel classification. Four weekly doses of 375 mg/m2 rituximab were applied. RESULTS: 38 patients from eight centers were included between January 1997 and January 1998 and were evaluable for response and toxicity on an intention to treat basis. The median age was 55 years (range 26-75 years). Thirteen patients (35%) were in first relapse, 11 patients (30%) in second, and 13 patients (35%) in third relapse. The median time between primary diagnosis and study entry was 4.6 years (range 0.9-14.7 years). Twenty-three patients tolerated the application of rituximab without adverse events; in 13 cases the infusion rate had to be reduced because of side effects; in two patients the application was stopped because of pharyngeal edema and anaphylactoid reaction. The most frequent side effects were fever (13 patients) and rigor (13 patients); 65% of the side effects were observed after the first infusion. Twenty grade-III/IV side effects were considered to be related to treatment: lymphocytopenia (3), granalocytopenia (1), thrombocytopenia (2), fever (1), hyperglycermia (1), venous thrombosis (1), syncope (1), plasmatic coagulation disorder (1), shortness of breath (2), photosensitivity (1), cardiac failure (1), chills (1), sepsis (1), tumor lysis (1), anemia (1), and pharyngeal edema (1). Eight patients were not eligible for assessment of response because of non-follicular subtypes of low-grade lymphomas (n =6) or early termination of therapy at the first infusion because of severe side effects (n =2). From the 30 evaluable cases with follicular lymphomas, five patients achieved a complete remission (CR) (17%), nine patients a partial remission (PR) (30%), and two patients a minor response (MR) (7%). The overall response rate was 47%. The median time to treatment progression (TTP) was 201 days (range 64-293 days), with five patients experiencing long-lasting remissions of 214-293 days duration. In three patients, the rituximab-induced remission exceeded the preceding progression-free interval substantially. Bulky disease (P=0.058) and/or bone-mar row involvement (P=0.046) were associated with poor response. CONCLUSION: This study confirms the moderate treatment-related toxicity and the high antilymphoma activity of rituximab in patients with relapsed follicular lymphoma. Further studies are needed to determine the role of rituximab in the first-line treatment of these disorders and its combination with conventional chemotherapy.

Adult↗
PubMed2000

Recent advances in antigen-targeted therapy in non-Hodgkin's lymphoma.

Substantial advances in antigen-targeted lymphoma therapy have been achieved in recent years that make the use of monoclonal antibodies a highly attractive concept and promise further improvements in the clinical management of malignant lymphoma. The development of the chimeric anti-CD20 antibody IDEC-C2B8 (Rituximab) proved the concept of an effective therapy with a single unconjugated monoclonal antibody in lymphoma patients. Radioimmunoconjugates with myeloablative activity induced response rates of 80-100% in heavily pretreated patients. Progress in the genetic engineering of immunotoxins has improved the efficacy of these constructs. Ongoing prospective clinical trials will define the optimal use of these innovative therapeutic agents in patients with malignant lymphoma, and may establish therapeutic strategies with a high anti-lymphoma specificity and a low unspecific toxicity.

Antibodies, Bispecific↗
PubMed2000

Impact of the simultaneous administration of the (+)- and (-)-forms of formyl-tetrahydrofolic acid on plasma and intracellular pharmacokinetics of (-)-tetrahydrofolic acid.

PURPOSE: To detect possible interactions between (-)-formyl-tetrahydrofolic acid (leucovorin, (-)-fTHF) and (+)-formyl-tetrahydrofolic acid ((+)-fTHF) on the plasma and intracellular pharmacokinetics following their simultaneous administration. METHODS: Plasma levels of (-)-fTHF, (-)-methyl-THF, and (+)-fTHF were determined in samples from four volunteers following the administration of both (-)-fTHF and (+/-)-fTHF and in seven patients during a 5-fluorouracil (5-FU)/fTHF combination chemotherapy. In addition, the intracellular uptake of (14)C-(-)-mTHF in the presence of (+)-mTHF at increasing concentrations was measured in vitro. Analyses were performed using a highly specific high-performance liquid chromatography procedure. RESULTS: The pharmacokinetic parameters obtained for (-)-fTHF following the administration of (-)-fTHF only were: terminal half-life, 1.2 h; area under the curve, 10 microg. h/ml; maximum concentration, 12 microg/ml; clearance, 305 ml/min; volume of distribution, 19 l. The parameters did not differ significantly as compared with those obtained following the administration of (+/-)-fTHF to both volunteers and patients. There were no differences in the pharmacokinetics of (-)-mTHF or in the protein binding of both substances with the different forms of administration. The intracellular uptake of (14)C-(-)-mTHF did not depend on the presence of (+)-mTHF at either concentration. CONCLUSIONS: These data suggest that (-)-fTHF is not therapeutically superior to (+/-)-fTHF and that the latter is appropriate during combination chemotherapy with 5-FU/fTHF in patients with colorectal cancers.

Adult↗
PubMed2000

Multivariate analysis of prognostic factors in patients with refractory and relapsed acute myeloid leukemia undergoing sequential high-dose cytosine arabinoside and mitoxantrone (S-HAM) salvage therapy: relevance of cytogenetic abnormalities.

To improve the basis for the stratification of patients with refractory and relapsed acute myeloid leukemia (AML) univariate and multivariate analyses of prognostic factors were performed in 254 patients (median age 50 years, range 18-74) undergoing S-HAM salvage chemotherapy during two consecutive prospective trials of the German AML Cooperative Group. In a multivariate analysis, duration of the first complete remission (CR) was the only factor associated with time to treatment failure (P = 0.0223). Disease-free survival was influenced by a short duration of the first CR of less than 6 months (P = 0.0001), WBC (P = 0.0018), blast count (P = 0.0037), and neutrophil count (P = 0.0119). The achievement of CR was related to the hemoglobin level only (P = 0.0457), the early death rate was related to age only (P = 0.0109), and survival was related to the bilirubin level only (P = 0.0166). In the subgroup of 104 patients in whom additional karyotype analyses were performed prior to first-line therapy unfavorable chromosome abnormalities were associated with a lower CR rate (univariate analysis, P = 0.0342; CR 24% vs 53%) and were the only factor related to survival. These analyses warrant the further evaluation of the impact of cytogenetic abnormalities on the outcome of patients with advanced AML in order to improve the characterization according to duration of first CR and to WBC of distinct subgroups of patients with differing prognoses as a basis for stratification in future trials.

Adult↗
PubMed2000

Successful modulation of high-dose cytosine arabinoside metabolism in acute myeloid leukaemia by haematopoietic growth factors: no effect of ribonucleotide reductase inhibitors fludarabine and gemcitabine.

High-dose cytosine arabinoside (AraC)-containing regimens have shown the highest antileukaemic efficacy of all currently used regimens in the treatment of acute myeloid leukaemia (AML). This study aimed at increasing the antileukaemic potential of high-dose AraC by raising intracellular levels of AraC triphosphate (AraCTP), which is the mediator of cytotoxicity, via biochemical modulation by inhibitors of ribonucleotide reductase (RR) or haematopoietic growth factors (HGFs). Blasts from patients with de novo AML were analysed for their formation of AraCTP under high-dose AraC conditions (20 microM over 3 h) without prior modulation (n = 47) after a 2-h pre-exposure with fludarabine (50 microg/ml) (n = 40) or gemcitabine (30 ng/ml) (n = 40) and after a 48-h pre-exposure to granulocyte colony-stimulating-factor (G-CSF; 100 ng/ml) (n = 27) or granulocyte-macrophage colony-stimulating-factor (GM-CSF; 100 U/ml) (n = 28). Unmodulated formation of AraCTP (median 239.8 ng/107 cells) could not be increased via modulation by gemcitabine (232.4 ng/107 cells) or fludarabine (247.8 ng/107 cells). The lack of effect of RR inhibitors was also observed for all other known metabolites of AraC [Ara-cytosine monophosphate (CMP), Ara-cytosine diphosphate (CDP), AraCDP-choline, Ara-uridine monophosphate (UMP), Ara-uridine diphosphate (UDP) and Ara-uridine triphosphate (UTP)]. In contrast, pre-exposure to HGFs led to significant increases in AraCTP formation (G-CSF 556.0 ng/107 cells, 2.31-fold increase, P < 0.001; GM-CSF 447.9 ng/107 cells, 1.87-fold increase, P < 0.0001). To establish the mechanism responsible for these effects, the activity of the rate-limiting enzyme of AraC metabolism, deoxycytidine kinase (dCK), was investigated (n = 33). In vivo exposure to GM-CSF led to increases in dCK activity from unmodulated values at 0 h (29.8 pmol/min/mg protein) to 34.3 pmol/min/mg protein at 24 h (1.15-fold increase) and 54.5 pmol/min/mg protein at 48 h (1. 83-fold increase). The raise in dCK activity over 48 h was significant (P < 0.013).

Arabinofuranosylcytosine Triphosphate↗
PubMed1999

Monoclonal antibody therapy for B cell non-Hodgkin's lymphomas: emerging concepts of a tumour-targeted strategy.

Although much progress has been made in the understanding of the pathobiology of malignant lymphomas in recent years, progress in the treatment of patients with this diagnosis has been limited. Monoclonal antibody therapy is an innovative and promising concept in the treatment of malignant lymphoma, and the current status of this treatment is reviewed here. Phase I/II clinical trials have proven the high antilymphoma activity of antibody-based therapeutic strategies. Radioimmunoconjugates with myeloablative activity have induced response rates of between 80 and 100% in heavily pretreated patients. The chimeric monoclonal antibody IDEC-C2B8 has shown high antilymphoma activity in patients with relapsed follicular lymphoma with an overall response rate of up to 50%. The combination of the IDEC-C2B8 antibody with standard chemotherapy has shown encouraging results with no increase in toxicity compared with chemotherapy alone. The introduction of antibody therapy promises to open new perspectives in the treatment of patients with malignant lymphoma. Prospective randomised clinical trials will define the patient who will gain maximal benefit from antibody-based therapy.

Antibodies, Monoclonal↗
PubMed1999

Hypercoagulability in a patient with hypodysfibrinogenemia: implications for clinical management.

Dysfibrinogenemia accounts for approximately 0.7% of thrombophilia in patients with venous thromboembolic disease. In 20% of these patients, plasma thrombophilic dysfibrinogen is below 1.0 mg/ml, defining hypodysfibrinogenemia. We describe a young female patient, in whom hypodysfibrinogenemia was the cause of several severe thromboembolic events which occurred even under oral anticoagulation monitored by a standard prothrombin time (PT) test. In this patient, the standard PT test according to Quick underestimated the plasma coagulability in vivo, presumably due to the low levels of dysfunctional fibrinogen as the substrate of the thromboplastin reagent. A PT test supplemented with bovine plasma fibrinogen (Thrombotest) revealed lower fibrinogen-independent international normalized ratio (INR) values in the proposita on oral anticoagulation compared to a control group with eufibrinogenemia. Monitoring therapy with the fibrinogen-independent Thrombotest secured safe anticoagulation in this patient. We suggest to consider PT tests with exogenous fibrinogen (e.g. Thrombotest) to monitor oral anticoagulation in the rare thrombophilic patients with hypodysfibrinogenemia.

Adult↗
PubMed1998

Activated protein C resistance and factor V Leiden in patients with hemolysis, elevated liver enzymes, low platelets syndrome.

OBJECTIVE: Hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome is characterized by a distinct activation of the coagulation system. A mutation of the gene coding for coagulation Factor V (Factor V Leiden) has been identified as the most frequent risk factor for thrombosis. To identify risk factors for HELLP syndrome, we determined coagulation parameters and the Factor V Leiden mutation in women who previously had developed HELLP syndrome. METHODS: Coagulation parameters (activated protein C resistance, antithrombin, protein C, protein S) were determined in 21 women 6 months to 9 years after they had developed HELLP syndrome in the third trimester. In addition, these women were analyzed for the presence of the Factor V Leiden mutation. RESULTS: Of these analyzed women, 33% (seven of 21) had an activated protein C resistance (activated protein C ratio less than 2.0). Another 38% of the women had subnormal activated protein C ratios (2.0-2.3). Only 57% of the women with an activated protein C resistance were identified as heterozygous carriers of the Factor V Leiden mutation (four of seven). CONCLUSION: Women with HELLP syndrome have a higher incidence of Factor V Leiden mutations. This increased incidence does not, however, account fully for the increased frequency of activated protein C resistance in these patients.

Adult↗
PubMed1998

Mantle-cell lymphomas have more widespread disease and a slower response to chemotherapy compared with follicle-center lymphomas: results of a prospective comparative analysis of the German Low-Grade Lymphoma Study Group.

PURPOSE: To compare mantle-cell lymphomas (MCLs) and follicle-center lymphomas (FCLs) for their features of clinical presentation, response to chemotherapy, and prognosis on the basis of a prospective randomized clinical trial. PATIENTS AND METHODS: Patients with MCL and FCL who entered onto the prospective randomized comparison of cyclophosphamide, vincristine, and prednisone (COP) versus prednimustine and mitoxantrone (PmM) followed by a second randomization for interferon (IFN) maintenance versus observation only. RESULTS: One hundred sixty-five of 234 patients had FCL and 45 of 234 patients had MCL. With FCL, both sexes were equally affected (men, 47%); patients with MCL were predominantly men (78%; P < .0004) and had a higher median age (64 v 53 years; P < .0001). Patients with MCL also had more widespread disease, reflected by the proportion of patients with two or greater extranodal manifestations (43% v 21%; P < .005) and nine or greater involved nodal areas (64% v 45%; nonsignificant [NS]). Response to chemotherapy was significantly lower in patients with MCL (complete remission [CR] + partial remission [PR], 69% v 88%; P < .05) and occurred at a slower pace. Patients with MCL also had a shorter event-free interval (median, 8 v 24 months; P < .0001) and overall survival (median, 28 v 77 months; P < .0001). In both subtypes, however, patients with less than two residual lymphoma manifestations in remission experienced a relatively good prognosis with an estimated 5-year survival of greater than 60% for MCL and greater than 75% for FCL. CONCLUSION: MCL and FCL differ substantially in their features of presentation, response to chemotherapy, and long-term prognosis. The extent of residual disease after completion of chemotherapy discriminates patients with different prognosis and may be used for the stratification of postremission strategies.

Adult↗