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Biomedical subjects

W Hiddemann

Publications and source records attributed to W Hiddemann.

At least 343 records · Page 19Linked to original sources
PubMed1991

Antifungal treatment by amphotericin B and 5-fluorocytosine delays the recovery of normal hematopoietic cells after intensive cytostatic therapy for acute myeloid leukemia.

Systemic fungal infections are recognized at increasing frequency during the course of intensive therapy for acute leukemias and require parenteral antifungal treatment mostly by amphotericin B (ampho B) alone or in combination with 5-Fluorocytosine (5-FC). Because of the potential myelosuppressive side effects of 5-FC it was the aim of the current study to evaluate the recovery of hematopoietic cells after intensive antileukemic therapy in patients receiving ampho B and 5-FC treatment for proven or suspected systemic fungal infections. The study population comprised 87 patients who were treated by standard chemotherapy for acute myeloid leukemia (AML) at first diagnosis or relapse. Twenty-two patients underwent systemic antifungal therapy consisting of ampho B (3 to 10 mg/kg/d) and 5-FC (150 mg/kg/d) for 3 to 33 days (median, 12 days). The remaining 65 patients served as controls to assess the hematologic recovery time (TR) as defined by the interval between the onset of chemotherapy and the post-treatment rise of granulocyte levels to greater than 500 cmm and thrombocyte levels to greater than 20,000 cmm. In patients receiving antifungal therapy, a significant prolongation of TR was observed with a median TR of 29 days compared with a median TR of 24 days (P = 0.0016) for the control group. No correlation was found between TR and the total dose of either ampho B or 5-FC or the type of antileukemic regimen. A possibly direct myelosuppressive effect of a fungal infection was unlikely to explain the findings because the ampho B/5-FC treatment was started in patients with proven or only suspected fungal infections, causing a similar delay of TR in both groups. The present data strongly suggest a myelosuppressive effect of ampho B/5-FC antifungal treatment in patients after intensive chemotherapy for acute leukemias.

Acute Disease↗
PubMed1991

Cytosine arabinoside in the treatment of acute myeloid leukemia: the role and place of high-dose regimens.

Cytosine arabinoside (AraC) is one of the most active drugs in the treatment of acute leukemias and is widely applied at all phases of therapy. In spite of extensive clinical and experimental investigations, its intracellular metabolism and especially its mechanism of action are still not fully elucidated. Controversy also continues about the most appropriate way and dose of administration; which differs by more than 100 fold in clinical studies ranging from low-dose, over standard and intermediate dose regimens, to high-dose protocols. The present review is focused on the role and place of high-dose AraC treatment in acute myeloid leukemia (AML). Based on available clinical and experimental data, the following conclusions can be drawn: Not considering possible but not yet demonstrated beneficial long-term effects, the incorporation of high-dose AraC into induction therapy has not resulted in an improvement of overall remission rate, with the possible exception of patients with slow initial cytoreduction after a first course of conventional treatment. Promising results, however, emerge from high-dose AraC-based consolidation protocols, which need confirmation in prospectively randomized comparative trials. In relapsed and refractory AML, higher than conventional doses undoubtedly enhance the efficacy of AraC salvage therapy. The question of whether the antileukemic activity of intermediate-dose regimens with 500-1,000 mg/m2 AraC is equivalent to that of high-dose protocols applying 2,000-3,000 mg/m2 AraC, however, remains open but may soon be answered by ongoing controlled clinical and pharmacologic investigations.

Cytarabine↗
PubMed1991

Treatment of advanced chronic lymphocytic leukemia by fludarabine. Results of a clinical phase-II study.

In a clinical phase-II study fludarabine phosphate was given to 20 patients with advanced chronic lymphocytic leukemia who had failed on prior conventional therapy. Fludarabine was administered at a dose of 25 mg/m2/d for 5 days. Treatment cycles were repeated every 4 weeks until maximal response, followed by two cycles for consolidation. Four of the 20 patients achieved complete remission and seven patients partial remission, resulting in an overall response rate of 55% (11/20). Fludarabine therapy was well tolerated, with mild myelosuppression and secondary infections comprising the predominant side effects. These data warrant further confirmation and a randomized comparison of fludarabine with established regimens, which is currently underway.

Adult↗
PubMed1991

Reversible leukaemic regrowth under GM-CSF treatment after chemotherapy for AML.

A 78-year-old woman with acute myelogenic leukaemia (AML M5 (FAB)) was treated with standard induction chemotherapy followed by recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) (250 micrograms/m2/day) in an effort to accelerate neutrophil recovery. After 10 days of rhGM-CSF therapy, increasing numbers of promonocytes and monocytes were detected in the peripheral blood, with a maximum total white blood count of 14,900/microliters of which 39% were promonocytes, 39% monocytes, and only 3% neutrophils. The bone marrow during GM-CSF therapy was hypercellular and contained 95% monocytic forms. After discontinuation of rhGM-CSF, this monocyte lineage stimulation was completely reversible. Without further chemotherapy the patient entered a complete remission after 9 months and is now relapse free after 24 months. Since the stimulation was restricted to the previously leukaemic lineage of this patient, the profound monocytosis observed in this case suggests the possibility that GM-CSF may exert reversible effects on the proliferation of clonogenic cells in acute monocytic leukaemia.

Aged↗
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↗
PubMed1991

Further thoughts on 'cell kill' in acute leukemia.

With traditional therapy of acute myelogenous leukemia, not more than 20% of patients achieve long-term survival. Efforts at intensifying postinduction chemotherapy have resulted in minor improvements only, but this limited progress has been hampered by increasing toxic-death rates. Eradication of the leukemia burden may be achieved by the introduction of more effective induction regimes and these may be rendered more effective by the application of 'enhancers'. With a lower tumor burden, and with more appropriate timing for supralethal therapy, it may be possible to achieve cure with greater frequency. Measurement of 'minimal residual disease' permits more logical selection of postinduction therapy.

Bone Marrow Transplantation↗
PubMed1991

In vitro and in vivo effects of rh GM-CSF in acute myeloid leukemia (AML).

70% of patients with newly diagnosed and 50% of patients with relapsed acute myeloid leukemia (AML) can achieve a complete remission with intensive chemotherapy. However, the treatment-associated mortality can be as high as 30% increasing with age, previous chemotherapy and intensity of chemotherapy. GM-CSF was first applied in 36 patients with high risk AML after chemotherapy to reduce the time of critical neutropenia. The early death rate was significantly lower in the GM-CSF group compared to 56 patients of a historic control group with similar risk factors and identical chemotherapy (p less than 0.009). The rate of complete remissions was also significantly higher in the GM-CSF group (p less than 0.09). More recently, GM-CSF was used as a priming agent 24 h prior to start of chemotherapy. 25 patients have entered the study up to now. The cell biological effects of GM-CSF in vivo include an immediate increase of leukemic blasts and of normal myeloid cells in the peripheral blood with a median of 2.0, an increase of cells in the S-phase of the cell cycle in bone marrow biopsies, an increase in DNA polymerase activity, an increase in Ara-C cytotoxicity and immunophenotypic changes compatible with differentiation of leukemic blasts along the pathway of normal myeloid progenitors. GM-CSF has a dual effect on normal and leukemic myeloid cells. It can be safely applied in patients with AML. Prospective randomized trials have to be performed to establish its role in reducing treatment toxicity and in improving the overall treatment results.

Acute Disease↗
PubMed1991

Flow cytometric characterization of acute myeloid leukemia. Part 1. Significance of light scattering properties.

Acute leukemias are classified using the morphological and cytochemical criteria set forward by the French, American and British (FAB) group. Immunophenotyping is helpful for the differential diagnosis but is secondary to the morphological criteria. Immunophenotyping performed by flow cytometry, however, can yield valuable information on cell morphology in addition to cell surface antigen expression. To provide a basis of a combined evaluation of both morphology, i.e. light scattering, and immunophenotype by flow cytometry we have compared the light scattering profiles of 70 patients newly diagnosed with acute leukemia with normal bone marrow and related the findings to the FAB classification. Three main light scattering profiles were observed in the bone marrow aspirates of the 70 patients (A1,2; B1,2,3; C1,2,3,4). A1,2, characterized by a predominant cell cluster with low forward and orthogonal light scattering, contained only and all patients diagnosed as acute lymphoblastic leukemia, acute undifferentiated leukemia, and acute non-lymphocytic leukemia M6 and M1. B1,2,3 is characterized by a predominant cell cluster with large forward and low to high orthogonal light scattering. Category B1 contained the majority of patients classified as M5; the M3 leukemias were categorized as B2. C1,2,3,4 is characterized by a predominant cell cluster with low forward and orthogonal light scattering that branches towards regions with larger light scattering. Categories C1 and C2 contained the majority of the patients classified as M2. Category C3 was specific for M4 and M4eo leukemias. The patients diagnosed as M4 were heterogeneous and equally distributed over the B and C categories. The clear relationship found between the FAB classification and classification by the light scattering profile of the acute leukemias enhances the importance of the flow cytometric classification of leukemias. In contrast with light microscopy, flow cytometry can now provide the hematologist with an objective technique to classify leukemias by the simultaneous assessment of cell surface antigen expression and cell morphology, i.e. light scattering.

Acute Disease↗
PubMed1990

Treatment of refractory Hodgkin's disease with high-dose cytosine arabinoside and mitoxantrone in combination. Results of a clinical phase II study of the German Hodgkin Study Group.

In the present study, the activity and side effects of high-dose cytosine arabinoside (HD-Ara-C) in combination with mitoxantrone (mitox) (HAM) was evaluated in 32 heavily pretreated patients with refractory Hodgkin's disease. Therapy consisted of HD-Ara-C 3 g/m2 every 12 hours days 1 and 2 and mitox 10 mg/m2/d days 3 to 5. In subsequent steps, HD-Ara-C was escalated to six and eight doses for 3 and 4 days, respectively, and mitox to four doses on days 2 to 5. Thirty-two patients 17 to 55 years of age entered the study. Twenty-five cases presented with extranodal disease and disseminated organ involvement and 21 revealed systemic (B) symptoms. Eighteen patients (56%) responded with five complete and 13 partial remissions, ten patients (31%) had refractory disease, and four patients died from infections during treatment-induced cytopenia. The predominant toxicity was severe myelosuppression in all patients with major infections occurring during 55% of treatment courses. Ten of the responding 18 patients underwent subsequent autologous (n = 9) or allogeneic bone marrow transplant (BMT). Seven of these cases are currently alive at 5+ to 22+ months, six of them without evidence of disease. Among the remaining eight patients not receiving BMT, three are alive at 6+ to 19+ months from the initiation of HAM, two of them in ongoing remissions of 2+ and 5+ months' duration. Two patients died from transplant-related complications and six patients succumbed to progressive disease following relapse. The median survival for all treated patients is 6.2 months. These data indicate that HAM has a significant activity in refractory Hodgkin's disease. However, the substantial side effects and the lack of an obvious superiority to alternative, less intensive regimens limits the further application of the two-drug combination in its present form. Modifications in timing and dosage and the addition of hematopoietic growth factors will be evaluated in subsequent trials.

Adolescent↗
PubMed1990

Mitoxantrone/high-dose Ara-C and recombinant human GM-CSF in the treatment of refractory non-Hodgkin's lymphoma. A pilot study.

Previous study has shown that the combination of mitoxantrone (Novantrone, NO) and Ara-C (AC) (NOAC) was active in refractory non-Hodgkin's lymphoma (NHL) but myelosuppression was dose-limiting. In a pilot study, we investigated the effects of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) after NOAC chemotherapy in patients with refractory NHL. NO was applied at a dosage of 10 mg/m2/day on days 2 and 3 and AC at 3 g/m2/12h on days 1 and 2. RhGM-CSF was administered at 250 ug/m2/day as a continuous i.v. infusion from day 6 until the neutrophils were greater than 3.0/nl for 3 consecutive days. Twenty-three patients from five of the nine participating centers were treated with NOAC chemotherapy plus rhGM-CSF, whereas 14 patients from the other four centers received chemotherapy alone. With rhGM-CSF, the median duration of severe neutropenia (less than 0.5/nl) after NOAC was 8 days versus a median of 13 days without rhGM-CSF (P = 0.0058), and that of thrombocytopenia (less than 20.0/nl), 3 days versus 7 days (P greater than 0.4, NS). The rates of infections and stomatitis were 25% and 17%, respectively, for patients treated with rhGM-CSF as compared to 53% (P = 0.0547, NS) and 60% (P = 0.0078), respectively, without rhGM-CSF. The following side effects were associated with the administration of rhGM-CSF: pleural and/or pericardial effusions in five patients, thrombosis in two patients, bone pain in two patients, and respiratory distress syndrome in one patient. A complete remission was achieved in nine of the 23 patients treated with NOAC plus rhGM-CSF, and in two of the 14 patients treated with chemotherapy alone. The median survival of patients treated with rhGM-CSF was not reached at 400 days and seemed to be longer than that of patients treated with chemotherapy alone (median, 109 days; P = 0.036). RhGM-CSF after chemotherapy can be applied safely to patients with NHL, shorten the period of severe cytopenia, reduce the rates of stomatitis, and did not seem to cause adverse effects on response.

Adolescent↗
PubMed1990

Effects of verapamil on anthracycline-induced cardiomyopathy: preliminary results of a prospective multicenter trial.

Previous investigations in animals and one retrospective study in man suggest that verapamil can prevent anthracycline-induced cardiomyopathy. In the following study, patients with acute myeloid leukemia (AML) treated with double induction and consolidation chemotherapy (AML COOP study 1986, [3]) were randomized in a group with and without accompanying low-dose oral verapamil treatment. Since July 1986, 64 patients have been included. Thirty patients have been evaluated for pre- and posttreatment cardiological investigations. So far, no significant difference in cardiotoxicity has been observed either between the verapamil and nonverapamil group or between the two induction chemotherapy regimens (TAD/TAD - TAD/HAM).

Adolescent↗
PubMed1990

Recombinant human granulocyte-macrophage colony-stimulating factor after chemotherapy for acute leukemias at higher age or after relapse.

Chemotherapy (CT) induced critical cytopenia remains as the major dose limiting problem in the treatment of acute leukemias. This is especially true in patients at high risk of early death due to high intensity chemotherapy for relapse or to higher age. In an attempt to reduce the phase of risk we administered human recombinant GM-CSF to 23 patients at a median age of 65 (range 17-84) years including 8 acute myelogenous (AML) and 5 lymphoblastic (ALL) leukemias after early or second relapses and 10 patients of 65 years and older in primary induction treatment for AML. 3 patients with AML had prior bone marrow transplantation. 4 AML's were secondary to tumor chemotherapy (2) or myelodysplastic syndrome (2). The study was part of chemotherapeutic phase II and III studies using TAD9 for primary induction chemotherapy and S-HAM for relapses. Starting on day 4 after the end of intensive CT GM-CSF 250 micrograms/m2/day was given by continuous i.v. infusion and after recovery of neutrophils was deescalated in two 4 day steps and discontinued. 12/23 patients achieved a complete remission (CR) and median age of responders is 61 (range 17-84) years. In the group of the non-transplanted patients the median recovery time of neutrophils is reduced by one week when compared to controls receiving the same chemotherapy (p = 0.002). We observed a leukemic regrowth in 3 patients of 61, 70, and 78 years, 2 of whom having secondary AML. After discontinuation of GM-CSF the regrowth of blasts was reversible in 1 patient and continued unaffectedly in its kinetics in 2 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1990

Synergistic cytotoxicity of cytosine arabinoside and mitoxantrone for K562 and CFU-GM.

High-dose cytosine arabinoside (Ara-C) plus mitoxantrone (MX) have proved to be effective in the treatment of refractory acute leukemia. The optimal sequence of drug administration was tested in a clonogenic assay with the leukemic myeloid cell line K562, and with CFU-GM of normal human bone marrow. The exposure times were 24 h for Ara-C and 1 h for MX with 1 h delay between incubations. Either order of the drugs and a wide range of drug concentrations were tested. Cytotoxicity was quantified by the survival fraction (fs) of colonies scored on day 7 (K562) or day 14 (CFU-GM). Drug synergism was evaluated by a cooperative index (CI). CI less than 1 indicates synergism, CI = 1 summation, and CI greater than 1 antagonism of the cytotoxic drugs. In K562 the sequence Ara-C much greater than MX was significantly more toxic (3.68 logs cell kill, CI = 0.02) than MX much greater than Ara-C (2.64 logs kill, CI = 0.31). The highest synergism was found by adding MX during the last hour of a 24 h Ara-C exposure. For CFU-GM, Ara-C much greater than MX showed higher synergistic toxicity (2.24 log cell kill, CI = 0.23) than MX much greater than Ara-C (1.44 logs, CI = 1.11). The clinical high dose Ara-C/MX protocol was transformed into an in vitro model and tested on K562. The highest synergism was found after the sequence of 3 h Ara-C followed by 0.5 h MX after 8.5 h delay (1.73 logs kill, whole sequence 2.01 logs kill), thus supporting the clinically applied sequence.

Cells, Cultured↗