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  • 1
    Abstract: Outcome of patients with primary refractory acute myeloid leukemia remains unsatisfactory. We conducted a prospective phase II clinical trial with gemtuzumab ozogamicin (3 mg/m(2) intravenously on day 1), all-trans retinoic acid (45 mg/m(2) orally on days 4-6 and 15 mg/m(2) orally on days 7-28), high-dose cytarabine (3 g/m(2)/12 h intravenously on days 1-3) and mitoxantrone (12 mg/m(2) intravenously on days 2-3) in 93 patients aged 18-60 years refractory to one cycle of induction therapy. Primary end point of the study was response to therapy; secondary end points included evaluation of toxicities, in particular, rate of sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation. Complete remission or complete remission with incomplete blood count recovery was achieved in 47 (51%) and partial remission in 10 (11%) patients resulting in an overall response rate of 61.5%; 33 (35.5%) patients had refractory disease and 3 patients (3%) died. Allogeneic hematopoietic cell transplantation was performed in 71 (76%) patients; 6 of the 71 (8.5%) patients developed moderate or severe sinusoidal obstruction syndrome after transplantation. Four-year overall survival rate was 32% (95% confidence interval 24%-43%). Patients responding to salvage therapy and undergoing allogeneic hematopoietic cell transplantation (n=51) had a 4-year survival rate of 49% (95% confidence intervaI 37%-64%). Patients with fms-like tyrosine kinase internal tandem duplication positive acute myeloid leukemia had a poor outcome despite transplantation. In conclusion, the described regimen is an effective and tolerable salvage therapy for patients who are primary refractory to one cycle of conventional intensive induction therapy. (clinicaltrials.gov identifier: 00143975).
    Type of Publication: Journal article published
    PubMed ID: 27036160
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  • 2
    Keywords: CANCER ; SURVIVAL ; TOXICITY ; DEATH ; RISK ; COMPLEX ; MUTATIONS ; ABNORMALITIES ; ACUTE PROMYELOCYTIC LEUKEMIA ; TOPOISOMERASE-II ; RECOMMENDATIONS ; CELL TRANSPLANTATION ; MYELODYSPLASTIC SYNDROMES ; MITOXANTRONE ; SECONDARY LEUKEMIAS
    Abstract: To study the characteristics and clinical impact of therapy-related acute myeloid leukemia (t-AML). 200 patients (7.0%) had t-AML and 2653 de novo AML (93%). Patients with t-AML were older (P 〈 .0001) and they had lower white blood counts (P = .003) compared with de novo AML patients; t-AML patients had abnormal cytogenetics more frequently, with over-representation of 11q23 translocations as well as adverse cytogenetics, including complex and monosomal karyotypes, and with underrepresentation of intermediate-risk karyotypes (P 〈 .0001); t-AML patients had NPM1 mutations (P 〈 .0001) and FLT3 internal tandem duplications (P = .0005) less frequently. Younger age at diagnosis of primary malignancy and treatment with intercalating agents as well as topoisomerase II inhibitors were associated with shorter latency periods to the occurrence of t-AML. In multivariable analyses, t-AML was an adverse prognostic factor for death in complete remission but not relapse in younger intensively treated patients (P 〈 .0001 and P = .39, respectively), relapse but not death in complete remission in older, less intensively treated patients (P = .02 and P = .22, respectively) and overall survival in younger intensively treated patients (P = .01). In more intensively treated younger adults, treatment-related toxicity had a major negative impact on outcome, possibly reflecting cumulative toxicity of cancer treatment.
    Type of Publication: Journal article published
    PubMed ID: 21127174
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  • 3
    Keywords: THERAPY ; DIAGNOSIS ; TRIAL ; STEM-CELL TRANSPLANTATION ; CRITERIA ; RECOMMENDATIONS
    Abstract: To determine the prognostic impact of monosomal karyotype (MK) in acute myeloid leukemia (AML) in the context of the current World Health Organization (WHO) classification and to evaluate the outcome of MK+ patients after allogeneic hematopoietic stem cell transplantation (HSCT). Of 1058 patients with abnormal cytogenetics, 319 (30%) were MK positive (MK+). MK+ patients were significantly older (p=0.0001), had lower white blood counts (p=0.0006) and lower percentages of bone marrow blasts (p=0.0004); MK was associated with the presence of -5/5q-, -7, 7q-, abnl(12p), abnl(17p), -18/18q-, -20/20q-, inv(3)/t(3;3), complex karyotype (CK), and myelodysplasia (MDS)-related cytogenetic abnormalities (p〈0.0001, each); NPM1 mutations (p〈0.0001), FLT3 internal tandem duplications (p〈0.0001) and tyrosine kinase domain mutations (p=0.02) were less frequent in MK+. Response to induction therapy and overall survival in MK+ patients were dismal with a complete remission rate of 32.5% and a 4-year survival of 9%. MK retained its prognostic impact in AML with CK, AML with MDS-related cytogenetic abnormalities, and in a revised definition (MK-R) excluding cases with recurrent genetic abnormalities according to WHO classification and those with derivative chromosomes not leading to true monosomies. In younger patients allogeneic HSCT from matched related and unrelated donors resulted in a limited improvement of overall survival. These trials are registered at www.clinicaltrials.gov as NCT00151255 and NCT00151242.
    Type of Publication: Journal article published
    PubMed ID: 22096250
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Der Onkologe 4 (1998), S. 808-819 
    ISSN: 1433-0415
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Die CLL ist die häufigste Leukämie in den westlichen Ländern und ist eine Erkrankung des höheren Lebensalters. Sie ist charakterisiert durch eine Akkumulation von monoklonalen immuninkompetenten Lymphozyten im Knochenmark und peripheren Blut, ihre Ätiologie ist noch ungeklärt. Die Verdrängung der normalen Hämatopoese im Knochenmark führt im Verlauf der Erkrankung zu einer Knochenmarkinsuffizienz mit zunehmender Anämie, Thrombozytopenie und auch Neutropenie und den entsprechenden Symptomen. Diagnostik und Therapiemöglichkeiten sind Gegenstand dieser Arbeit.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-0584
    Keywords: Key words Gemcitabine ; Apoptosis ; Chronic lymphocytic leukemia ; Acute myeloid leukemia ; Cell lines ; HPLC
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Induction of apoptosis in vitro using gemcitabine (dFdC) in combination with cladribine (2-CdA) and other cytotoxic drugs on malignant mononuclear cells (MNCs) of patients with acute myeloid leukemia (AML, n=20) and chronic lymphocytic leukemia (CLL, n=20) in myeloid (HL60, HEL) and lymphatic cell lines (HUT78, JURKAT) was investigated using different incubation conditions (simultaneous and consecutive). Furthermore, the influence of dFdC on the level of intracellular metabolites of 2-CdA was studied using high-performance liquid chromatography (HPLC). Apoptosis was evaluated using flow cytometry with 7-aminoactinomycin D. In MNCs of patients with CLL, dFdC+2-CdA showed an antagonistic effect when applied simultaneously. This antagonism was reduced by consecutive application. The combination of dFdC with doxorubicin was synergistic, independent of incubation schedule. In blasts from newly diagnosed patients with de novo AML, all drug combinations (dFdC+2-CdA, doxorubicin, or cytosine arabinoside) were antagonistic by simultaneous incubation. Reduced antagonism or even synergism was shown (P〈0.001) by consecutive incubation. The simultaneous combination of dFdC with 2-CdA in all tested cell lines resulted in a competitive inhibition on the rate of apoptosis. By changing the incubation period to a consecutive schedule, the antagonism was diminished or synergism of apoptosis was measured (P〈0.001). Using similar incubation conditions, these experiments were supported by HPLC measurement of intracellular metabolites of 2-CdA influenced by dFdC application. In conclusion, we demonstrated that the efficacy of dFdC in vitro in combination with other cytotoxic drugs depends on the incubation condition and on the origin of neoplastic cells (lymphatic vs myeloid). The data suggest that simultaneous combination therapy with purine and pyrimidine analogues may not improve the clinical efficacy of one or the other drug administered alone.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-1289
    Keywords: Schlüsselwörter Hepatosplenomegalie ; Panzytopenie ; Reaktives Hämophagozytosesyndrom
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Zusammenfassung Ein 49jähriger Mann wird mit Fieber, Hepatosplenomegalie und Panzytopenie aufgenommen. In den bildgebenden Verfahren zeigt sich eine stark vergrößerte Milz mit multiplen inhomogenen Arealen. Bei hochgradigem V.a. Vorliegen eines isolierten Lymphombefalls der Milz erfolgt eine diagnostische Laparotomie mit Splenektomie. In der histologischen Aufarbeitung zeigt sich das Bild eines reaktiven Hämophagozytosesyndroms (RHPS) mit Beteiligung von Milz, milzhilären Lymphknoten, Leber und Knochenmark. Der Nachweis eines infektiösen Agens als Auslöser des RHPS gelingt nicht. Postoperativ kommt es zu einer raschen und anhaltenden Normalisierung des Blutbildes. Der Verlauf dieses Falls bestätigt die Schwierigkeit der Abgrenzung des RHPS von malignen Systemerkrankungen.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1569-8041
    Keywords: cladribine ; 2-CdA ; mantle-cell lymphoma ; treatment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: Cladribine (2-chlorodeoxyadenosine, 2-CdA) has been reported to be effective in the treatment of low-grade lymphomas. The objective of this multicenter study was to evaluate the activity of cladribine in mantle-cell lymphomas as first-line therapy or in first relapse using an intermittent two-hour infusion of cladribine. Patients and methods: A total of 47 courses, or an average of four courses per patient, were administered to 12 patients (seven untreated, five relapsed) with 5 mg/m2 cladribine given as an intermittent two-hour infusion over five consecutive days for a maximum of six cycles every four weeks. Results: Cladribine showed activity in patients with mantle-cell lymphomas, achieving a response rate of 58% (95% confidence interval (95% CI): 28%–85%). Myelosuppression was the major toxicity with 17% of grade 3 and 4 neutropenia. Thrombocytopenia was rare with only 2% of grade 3 and 4. Conclusion: These results demonstrate single-agent activity of cladribine in mantle-cell lymphomas using the intermittent two-hour infusion dosage regimen. To further improve treatment results, cladribine should be combined with other agents active in mantle-cell lymphomas.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1569-8041
    Keywords: chronic lymphocytic leukaemia ; epirubicin ; fludarabine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: Fludarabine has been reported to be the most effective single-agent in previously treated chronic lymphocytic leukaemia (CLL). Based on the in vitro synergism of fludarabine with anthracyclines and on results showing a higher efficacy of CHOP against COP we attempted to improve treatment results with a combination of fludarabine and an anthracycline. Patients and methods: The aim of the multicenter study was to evaluate the rate and duration of remissions and investigate the toxic and immunosuppressive effects of fludarabine and epirubicin in the treatment of CLL in Binet stages B and C as first-line therapy or in first relapse. Thirty-eight patients were treated with fludarabine 25 mg/m2 on days 1–5 and epirubicin 25 mg/m2 on days 4 and 5. Results: The overall response rate (OR) was 82% (95% confidence interval (95% CI): 66%–92%) with a CR rate of 32% (95% CI: 18%–49%). For the 25 previously untreated patients the OR was 92% (95% CI: 74%–99%) including 40% CRs (95% CI: 21%–61%). Granulocytopenia grade 3 occurred in 23% of all evaluable cycles, and grade 4 in 17%. The median remission duration was 19 months (range 6–37 months). Conclusion: The results show that the combination of fludarabine and epirubicin is tolerable and highly effective in the treatment of CLL. With the addition of epirubicin to fludarabine, it appears possible to achieve a higher response rate and a more rapid response, especially of nodal manifestations. This regimen can be administered in an outpatient facility except for the first cycle because of the risk of a tumour lysis. The possible benefit of the combination presented here in the treatment of CLL in comparison to single-agent fludarabine treatment is presently under study in a prospective randomised multicenter study.
    Type of Medium: Electronic Resource
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