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Biomedical subjects

W Hiddemann

Publications and source records attributed to W Hiddemann.

At least 361 records · Page 20Linked to original sources
PubMed1990

Treatment of relapsed acute lymphocytic leukemia in adults.

Thirty-three patients with ALL/AUL in first relapse were treated with an induction of prednisone, vindesine, daunorubicin, Erwinia asparaginase, i.t. MTX (phase I), high-dose cytarabine, and etoposide (phase II). Twenty-one (64%) achieved a complete remission, one a partial remission. Side effects of induction-phase I were predominantly hematological with subsequent infections and gastrointestinal toxicity. In phase II some patients had additional cutaneous, ocular, and hepatic toxicity. The treatment efficiently induced remissions with tolerable toxicity in relapsed ALL. The disease-free survival, however, needs to be improved.

Adolescent↗
PubMed1990

Analysis of the cellular DNA and RNA content in acute leukemias by flow cytometry.

In the present study bone marrow samples from 573 patients with newly diagnosed acute myeloid (AML) and lymphoblastic or undifferentiated leukemias (ALL/AUL), were analysed for their cellular DNA and DNA/RNA content, respectively, by means of flow cytometry. From 237 patients with AML 35.4% revealed aneuploid DNA stemlines. While no relation of DNA aneuploidy with other pretherapeutic parameters, including FAB subtype, white blood cell count, lactate dehydrogenase, S-phase index and percentage of blasts in the bone marrow, was observed, cases with aneuploid DNA stemlines revealed a tendency towards longer remission duration. In ALL/AUL 21.8% of 280 patients expressed DNA aneuploidies, which were less frequently found in T-cell ALL (11.1%) as compared to common(C)-ALL (21.4%) or null-cell(null)-ALL (23.5%). DNA aneuploidy was not related with other clinically defined risk factors such as age, white blood cell count, and rapid achievement of remission. Patients with DNA indices less than 1.0, however, tended to have shorter remissions. A significant difference in RNA indices was observed between AML and ALL/AUL with median values of 14.4 and 10.1, respectively (P less than 0.05). These data indicate the usefulness of flow cytometric analyses of cellular DNA and RNA content for the characterization and classification of acute leukemias, complementing the identification of clinical risk factors, immuno-phenotyping and cytogenetics.

Acute Disease↗
PubMed1990

Treatment strategies in acute myeloid leukemia (AML). B. Second line treatment.

The strategy for treatment of relapsed or refractory acute myeloid leukemia must primarily be based on the patient's age and clinical condition as well as on the stage of the disease. Accordingly, the general decision between an intensive approach including high-dose chemotherapy or possibly immediate allogeneic bone marrow transplantation versus less-aggressive palliative treatment will precede the selection of the most appropriate salvage regimen. In patients qualifying for intensive second-line chemotherapy the duration of the first remission and the number of relapses provide the means to discriminate between refractoriness or maintained responsiveness to conventional protocols. More than 50% of patients with first relapses after 6-12 months remission duration will respond to standard therapy again and should therefore not be entered on investigational agents with unproven antileukemic activity. The latter seems deeply warranted, on the other hand, for early relapses, second recurrences and resistant first relapses with a remission rate of less than 30% after conventional regimens. These guidelines not only provide an objective rationale for selecting the most appropriate strategy at relapse in individual patients. Furthermore, they facilitate interstudy comparisons and a better judgement of different treatment protocols.

Bone Marrow Transplantation↗
PubMed1990

Treatment strategies in acute myeloid leukemia (AML). A. First-line chemotherapy.

Chemotherapy remains the backbone of treatment in AML. Of all adult patients 65% go into remission and have a chance of longer survival and of even being cured. Among the responders, 25% can be cured by intensive and long-term chemotherapy. Since the effect of chemotherapy appears not to be limited to a special period of time, its antileukemic and curative potential could be further exploited by multiple-step chemotherapy combining double induction, intensified consolidation and long-term maintenance. Improved antimicrobial treatment and the use of hematopoietic growth factors may help making multiple-step chemotherapy practicable, thereby increasing the cure rate in AML.

Acute Disease↗
PubMed1990

Hepatosplenic candidiasis, a late manifestation of Candida septicaemia in neutropenic patients with haematologic malignancies.

Systemic candidiasis with Candida-induced abscesses, predominantly in the liver and the spleen, was diagnosed in 27 patients with haematologic malignancies after intensive cytostatic therapy. Specific features included septic fever unresponsive to antimicrobial therapy, hepatosplenomegaly with multiple lesions in the liver and spleen (diameter up to 2 cm) as detected by computed tomography (CT) or ultrasound, and an elevation in liver enzymes. During treatment, induced neutropenia, hepatic and splenic foci were poorly defined histologically and were not identified by imaging procedures. After granulocyte recovery these foci showed characteristic histological patterns. Ultrasound and/or CT investigations of the abdomen now revealed characteristic lesions in the liver and the spleen. Gamma-GT and alkaline phosphatase were early indicators of hepatic involvement in Candida septicaemia and were often already elevated in aplasia.

Abscess↗
PubMed1990

Changing response of clonogenic myeloid leukemia blasts to granulocyte-macrophage colony-stimulating factor (GM-CSF) during anti-leukemic therapy--a case report on the basis of a clinical phase II trial.

In a clinical phase II trial GM-CSF was applied to 23 patients with acute leukemias carrying a high risk of early death because of old age or advanced disease. Concomitant laboratory investigations included the analysis of colony assays for normal granulopoietic progenitors (CFU-GM) and leukemic CFU-L with and without the addition of GM-CSF, as well as DNA measurements by flow cytometry (FCM) for the detection of DNA-aneuploidies. The present analysis is focused on one particular patient with acute myeloid leukemia (AML) in whom the detection of a DNA aneuploidy provided the readily accessible means to monitor the response of leukemic blasts to induction chemotherapy and subsequent GM-CSF treatment in vivo complementing the colony assay analyses performed in vitro. Prior to therapy 60% of cells revealed a DNA aneuploidy with a DNA index of 1.26 and in-vitro exposure of leukemic bone marrow blasts to GM-CSF (100 U/ml) enhanced the growth of CFU-L and CFU-GM with a significantly higher stimulatory index for CFU-L (1:19 versus 1:5.5). Three days after the completion of two cycles of induction therapy with thioguanine, cytosine arabinoside and daunorubicin (TAD 9) a morphologic bone marrow evaluation revealed aplasia without leukemic blasts. By FCM DNA analysis, however, 8% residual aneuploid cells were found. No growth of CFU-L was observed at this time point neither spontaneously nor after the addition of GM-CSF which induced the growth of CFU-GM, only. In-vivo application of GM-CSF (250 micrograms/mg2/day by continuous 24-h infusion) led to the recovery of normal granulopoiesis without evidence of a concomitant stimulation of aneuploid leukemic cells. These data indicate a change in the susceptibility of leukemic blasts to GM-CSF before and after chemotherapy. A reduction of the leukemic cell burden below a critical level or a selection of GM-CSF non-responsive early leukemic precursor cells may account for these observations.

Aged↗
PubMed1990

High-dose versus intermediate-dose cytosine arabinoside in combination with mitoxantrone for the treatment of relapsed and refractory acute myeloid leukemia--preliminary clinical and pharmacological data of a randomized comparison.

The present randomized trial addressed the pending question whether cytosine arabinoside (AraC) should be given at high or intermediate dose to patients with relapsed or refractory acute myeloid leukemia. Based upon the previously established regimen of the sequential administration of AraC and mitoxantrone (S-HAM) patients below 60 years of age were randomized to receive AraC at either 3.0 g/m2 vs. 1.0 g/m2 per dose while older patients were randomly assigned to either 1.0 g/m2 or 0.5 g/m2 AraC. Concurrent pharmacokinetic analyses were performed to determine the plasma AraC pharmacokinetics as well as the intracellular AraCTP peak concentrations and retention times. At the present stage 65 patients are evaluable for response and toxicity. Complete remissions were achieved at similar frequencies for patients treated with 3.0 g/m2 or 1.0 g/m2 AraC with 56% and 50%, respectively. Reasons for failure were different, however, with a higher incidence of resistant disease in patients treated with 1.0 g/m2 AraC and more early deaths in the higher dose treatment group. Pharmacokinetic studies indicated a homogeneous distribution of AraC plasma concentrations but a substantial interpatient variability for intracellular AraCTP peak concentrations and retention times.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Interventional antimicrobial strategy in febrile neutropenic patients. Results of a multicenter study in 1,260 patients with hematological malignancies. The Interventional Antimicrobial Strategy Study Group, Paul Ehrlich Society for Chemotherapy.

In a prospective, randomized multicenter trial of the Paul Ehrlich society different concepts for sequential empirical antimicrobial strategy for the treatment of patients with neutropenia less than 1.0/nl and fever greater than 38.5 degrees C and/or documented infection were studied. In phase I, patients with unexplained fever (FUO) were randomized for the combination of acylaminopenicillin plus aminoglycoside or third-generation cephalosporin plus aminoglycoside or double beta lactam therapy. Non-responders received additional vancomycin or all three substances of phase I in phase II. In phase III, all patients with persistent fever were then treated with amphotericin B plus 5-flucytosine and rifampin and randomized for the continuation of the double beta lactam regimen or additional imipenem/cilastatin. 667 (52.9%) of 1260 evaluable patients had FUO during the whole study period, of which 62.5% could be cured in phase I, 43.2% of non-responders in phase II and 55% of persistently febrile patients in phase III. The overall rate of complete response was 79.5%. 2.8% were non-responders, 11.7% were not evaluable for response and 40 patients (6%) died during the study, 24 (60%) of whom due to the underlying disease or the toxicity of antileukemic therapy. A significant difference between the treatment groups could not be detected in either of the three study phases.

Agranulocytosis↗
PubMed1990

Recombinant human GM-CSF following chemotherapy in high-risk AML.

Chemotherapy (CT) induced critical neutropenia remains a major dose limiting problem in acute leukemias. In order to reduce the phase of risk we gave recombinant human GM-CSF to 30 patients at high risk of early death with acute myeloid leukemia (AML). 19 patients with untreated AML and 1 patient with AML late relapse were 65+ years of age and were treated for CT by the TAD9 regimen. 10 patients at all ages had AML early or second relapse and received S-HAM CT. Starting on day 4 after CT GM-CSF 250 micrograms/m2/d was given by continuous i.v. infusion until neutrophils recovered. GM-CSF reduced the median recovery time of neutrophils by 4 days in the TAD9 and 9 days in the S-HAM CT group when compared to controls. After the CT induced aplasia 3 patients with AML showed a regrowth of their blasts which after the stop of GM-CSF was reversible in 1 patient and unaffectedly continued in 2 patients. 57% of patients attained a complete remission, and the median age of the responders was 65 (34-84) years. Remission duration was not found to be reduced. Thus, GM-CSF reduces CT toxicity with a low risk of promoting the disease and may allow more effective antileukemic treatment.

Adult↗
PubMed1990

Sequential studies on the role of mitoxantrone, high-dose cytarabine, and recombinant human granulocyte-macrophage colony-stimulating factor in the treatment of refractory non-Hodgkin's lymphoma.

Mitoxantrone (Novantrone, American Cyanamid Company; NO) and high-dose cytarabine (Ara-C; AC) have each been shown to be active in non-Hodgkin's lymphomas (NHL) in various studies. The studies reported here are sequential. The first study (NOAC I) combined high-dose cytarabine (3 g/m2/12 h as a 3 h infusion on day 1) with mitoxantrone (10 mg/m2/d on days 2 and 3). Of 31 patients with relapsed and refractory NHL, 7 achieved complete remission (CR) and 7, partial remission (PR). Myelosuppression was the major toxicity of this regimen. In the second study (NOAC II), the dosage of cytarabine was escalated to 3 g/m2/12 h on days 1 and 2 (4 doses) while mitoxantrone remained 10 mg/m2/d on days 2 and 3. The effects of recombinant human (rh) granulocyte-macrophage colony-stimulating factor (GM-CSF) were simultaneously studied. Twenty-three patients from five centers were treated with NOAC plus rhGM-CSF while 14 patients from four centers received NOAC II alone. A CR was achieved in 9 of 23 patients who received the additional rhGM-CSF and in 2 of 14 patients treated with NOAC alone. With rhGM-CSF, the median duration of severe neutropenia (less than 0.5/nL) after chemotherapy was 8 days versus a median of 13 days without rhGM-CSF, while the duration of severe thrombocytopenia (less than 20/nL) was not significantly different. The rates of infection and mucositis were 25% and 17%, respectively, with rhGM-CSF compared to 53% and 60% without rhGM-CSF. Thus, this last nonrandomized pilot study indicates that administration of rhGM-CSF reduces the duration of chemotherapy-induced cytopenia and the rate of mucositis. This growth factor does not appear to result in stimulation of lymphoma cells. At present, a controlled randomized trial is being conducted using NOAC II with rhGM-CSF or placebo to establish the definitive role of this growth factor in the treatment of NHL.

Adolescent↗
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↗
PubMed1990

Definition of refractoriness against conventional chemotherapy in acute myeloid leukemia: a proposal based on the results of retreatment by thioguanine, cytosine arabinoside, and daunorubicin (TAD 9) in 150 patients with relapse after standardized first line therapy.

Response to salvage therapy at first and second relapse was analyzed in 150 patients with acute myeloid leukemia (AML) to improve the characterization of relapsed AML and to deduce from this analysis a proposal for the definition of refractoriness against conventional therapy. Salvage treatment consisted of a repetition of the TAD 9 regimen which was already applied as induction protocol at initial diagnosis. All patients were recruited from the multicenter 1982 trial of the German AML Cooperative Group and had thus received a standardized first line treatment. Response at first relapse was significantly related to the duration of the first remission. From 38 patients relapsing within 6 months after successful induction therapy, only 11 (28%) achieved a second complete remission as compared to 58 of 98 (59%) cases with later occurring relapses (p less than 0.01). This difference was due to a significantly higher incidence of persistent leukemia in the former group and not biased by differences in early death rates. No other variable was found predictive for the response to salvage treatment including age, WBC, serum LDH, morphologic subtype, presence or absence of DNA aneuploidy as detected by flow cytometry or maintenance chemotherapy. A low remission rate of 28% was also obtained in the 14 patients at second relapse. These data indicate that patients with a duration of their first remission of more than 6 months cannot be considered as being refractory against standard chemotherapy while patients with early relapses and second recurrences have a response rate of less than 30% due to refractory disease. Hence, the following criteria are proposed for the definition of refractoriness against standard chemotherapy in advanced AML: (a) nonresponse to first-line induction therapy, (b) early relapse within 6 to 12 months of first remission, (c) relapse after 6 to 12 months of first remission and failure on a reinduction attempt with established regimens, (d) second and subsequent relapses. These criteria may provide a useful rationale for the selection of the most appropriate treatment at relapse. They may also serve as eligibility criteria for clinical phase I/II studies and will facilitate interstudy comparisons.

Adult↗
PubMed1990

Treatment of refractory acute lymphoblastic leukemia in adults with high dose cytosine arabinoside and mitoxantrone (HAM).

In a clinical phase II study the combination of high dose cytosine arabinoside and mitoxantrone (HAM) was applied to 24 patients with refractory acute lymphoblastic leukemia (ALL). All patients had received a standardized first line treatment and were considered refractory against conventional chemotherapy as defined by nonresponse to induction treatment (n = 8), nonresponse to an alternative salvage regimen at first relapse (n = 9), second and third relapses (n = 5) and relapse after bone marrow transplantation (n = 2). Therapy consisted of HD-araC 3 g/m2 q 12 hr days 1-4 and mitoxantrone 10 mg/m2/d days 2-5 or 2-6. Twelve of the 24 patients (50%) achieved a complete remission (CR), one patient had a partial remission, and five patients were nonresponders. Five patients died in aplasia due to infections, one additional patient succumbed to HD-araC related CNS toxicity. Nonhematologic side effects consisted predominantly in infection, nausea and vomiting, mucositis and diarrhea. Recovery of blood counts occurred at a median of 28 days from the onset of treatment; the median time to CR was 33 days. Three of the 12 responders underwent subsequent bone marrow transplantations and one is alive disease free at 40+ months. The median remission duration for the remaining nine patients is 3.5 months, with one case in ongoing CCR at 36+ months; the median survival time is 5 months. Considering the selection of a highly unfavorable group of patients, these data demonstrate a significant antileukemic activity of HAM in refractory ALL and support its application as consolidation treatment during first line ALL therapy.

Adolescent↗