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  • 1
    Language: English
    In: Annals of Hematology, 21 July 2010, Vol.90(4), pp.473-475
    Description: Dear Editor, We report on two patients with acute myeloid leukemia (AML) initially presenting in 2007. Both patients were tested positive for the FLT3-ITD mutation and were therefore treated with the FLT3 tyrosine kinase inhibitor sorafenib (400 mg/day) after progress of AML following several protocols of conventional chemotherapy. Both patients responded with a significant reduction of peripheral blast counts after 10 to 17 days leading to hematological response for 12 and 14 weeks, respectively. At the time of relapse, molecular analysis investigating mutations of both tyrosine kinase domains by sequencing of each individual FLT3-ITD cDNA did not demonstrate any additional mutations. We therefore suggest that the secondary resistance to sorafenib is mediated by other mechanisms than the acquisition of secondary mutations of FLT3 in these patients. FLT3-ITD mutations represent the second most frequent molecular aberration in AML leading to a constitutive activity of the class III receptor tyrosine kinase FLT3. FLT3-ITD mutations can be found in 25–30% of all AML patients and are associated with a reduced disease-free survival and overall survival [1–3].
    Keywords: Medicine ; Medicine
    ISSN: 0939-5555
    E-ISSN: 1432-0584
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  • 2
    Language: English
    In: Journal of Cancer Research and Clinical Oncology, 2014, Vol.140(8), pp.1391-1397
    Description: Byline: Ulf Schnetzke (1), Peter Fix (3), Baerbel Spies-Weisshart (1), Karin Schrenk (1), Anita Glaser (2), Hans-Joerg Fricke (1), Paul Rosee (1), Andreas Hochhaus (1), Sebastian Scholl (1) Keywords: AML; Relapse; FLT3; Cyclophosphamide; Stem cell transplantation Abstract: Background Approximately, 70 % of adult patients with de novo acute myeloid leukemia (AML) achieve a complete remission (CR) while 10--20 % of AML are refractory to induction chemotherapy. Furthermore, a significant proportion of AML patients in CR will relapse during or after consolidation treatment. There is no evidence for a standard salvage regimen and most centers use a combination of an anthracycline and cytarabine (AraC). The aim of this study was to investigate the impact of two age-adjusted regimens containing AraC and cyclophosphamide applied for the treatment of relapsed or refractory AML. Patients and methods We retrospectively analyzed 60 patients (24 male, 36 female median age 56 years) with relapsed or refractory AML who were treated with a combination of AraC and cyclophosphamide monocentrically between October 2000 and January 2013. Two different protocols containing either high-dose (hAC) or intermediate-dose cytarabin (iAC) have been applied dependent on age and performance status. Results We demonstrate an overall response rate (CR + PR) induced by hAC and iAC of 56.7 %. Importantly, a complete remission rate (CR + CRp) of 52.2 % was found in patients who received the hAC regimen while only 8.8 % of patients achieved a CR following the iAC protocol (p 〈 0.001). The rate of refractory disease was 26.1 and 47.1 %, respectively. High-risk cytogenetics, i.e., a complex aberrant or monosomal karyotype had no effect on achievement of CR after hAC. In addition, there was no impact of activating FLT3 mutations on response to treatment according to the hAC regimen. In the cohort of patients treated with the iAC protocol, treatment-related mortality of 11.8 % within 60 days was observed but none of the patients who received the hAC regimen died within the first 2 months following chemotherapy. The toxicity profile was acceptable at both cytarabine dose levels. Importantly, 19 patients (82.6 %) of the hAC cohort underwent allogeneic hematopoietic stem cell transplantation (HSCT) as consecutive treatment. Conclusion The hAC regimen represents a promising therapeutic approach to induce a second CR in younger patients with relapsed or refractory AML prior to HSCT without using anthracyclines. Author Affiliation: (1) Abteilung Hamatologie und Internistische Onkologie, Klinik fur Innere Medizin II, Universitatsklinikum Jena, Erlanger Allee 101, 07747, Jena, Germany (2) Institut fur Humangenetik, Universitatsklinikum Jena, Jena, Germany (3) Abteilung Internistische Onkologie und Hamatologie, Zentralklinik Bad Berka, Bad Berka, Germany Article History: Registration Date: 28/03/2014 Received Date: 12/03/2014 Accepted Date: 28/03/2014 Online Date: 12/04/2014 Article note: Ulf Schnetzke and Peter Fix have contributed equally to this work.
    Keywords: AML ; Relapse ; FLT3 ; Cyclophosphamide ; Stem cell transplantation
    ISSN: 0171-5216
    E-ISSN: 1432-1335
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  • 3
    Language: English
    In: Journal of Cancer Research and Clinical Oncology, 2009, Vol.135(4), pp.491-505
    Description: The role of different cytogenetic changes has been extensively evaluated in patients with acute myeloid leukemia (AML), and cytogenetic analysis of AML blasts is essential to form prognostic subgroups in order to stratify for the extent of therapy. Nevertheless, 40–45% of AML patients lack such cytogenetic markers, i.e., cytogenetically normal AML (CN-AML). In the past decade, different molecular aberrations were identified in AML and especially CN-AML can now be discriminated into certain prognostic subgroups. This review considers the latest advances to define the prognostic impact of molecular aberrations in AML and gives insights how such molecular markers can be applied for analysis of minimal residual disease. Furthermore, therapeutic implications as well as the potential role of new methodological techniques in analyzing expression patterns of AML blasts are discussed.
    Keywords: AML ; MRD ; Mutations ; Prognosis
    ISSN: 0171-5216
    E-ISSN: 1432-1335
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  • 4
    Language: English
    In: International journal of oncology, February 2009, Vol.34(2), pp.417-23
    Description: Acute myeloid leukemia (AML) is a heterogeneous disease with respect to clinical prognosis and acquired chromosomal aberrations. After routine banding cytogenetic analysis 45% of AML patients show a normal karyotype (NK-AML). For a better understanding of development and progression in AML, it is important to find markers which could be primary genetic aberrations. Therefore, in this study 31 patients with NK-AML were analyzed by new high resolution molecular cytogenetic approaches. A combination of multitude multicolor banding and metaphase microdissection-based comparative genomic hybridization revealed deletions of the subtelomeric regions in 6% of the studied cases. According to these results, locus-specific probes for the subtelomeric regions of chromosomes 5, 9, 11, 12 and 13 were applied on 22 of the studied 31 NK-AML cases. Surprisingly, 50% of them showed deletions or duplications. These aberrations occurred in the in vitro proliferating as well as in the non-proliferating cells. Meta-analysis of the aberrant regions revealed that they often include genes known to be associated with tumors, e.g. RASA3 on chromosome 13. These results implicate that aberrations in the subtelomeric regions of NK-AML occur quite often and may be considered as primary genetic changes, and should not be neglected in future diagnostic approaches.
    Keywords: Chromosome Aberrations ; Leukemia, Myeloid, Acute -- Genetics ; Telomere -- Genetics
    ISSN: 1019-6439
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  • 5
    In: European Journal of Haematology, March 2008, Vol.80(3), pp.208-215
    Description: Nucleophosmin (NPM1) and Flt3 internal tandem duplications (Flt3‐ITD mutations) represent the most frequent molecular aberrations in patients with acute myeloid leukemia (AML). While NPM1 mutations are associated with favourable prognosis in younger AML patients, Flt3‐ITD mutations reflect an unfavourable prognostic factor in these patients. So far, especially NPM1 mutations have not yet been evaluated exclusively in older patients. We retrospectively analysed the prevalence of NPM1 and Flt3‐ITD mutations and its association with complete remission (CR), and survival in 99 elderly patients (median age 71 yr, range 60–85 yr) newly diagnosed for AML. Primary treatment approach was curative in 54, and palliative in 38 patients, while seven patients received best supportive care only. The mean follow‐up of surviving patients was 600 d. Sixty‐seven patients were tested negative for NPM1 and Flt3‐ITD mutations (group 1), 16 patients carried only a NPM1 mutation (group 2) and nine patients had only a Flt3‐ITD mutation (group 3) while additional seven patients were positive for both aberrations (group 4). We can demonstrate a significant higher rate of CR comparing wildtype vs. NPM1 positive patients (40.5% for group 1 vs. 80.0% for group 2,  = 0.03) for patients receiving curative therapy. Interestingly, there is no significant difference in overall survival between group 1 and group 2 (Log‐rank test  = 0.22, median 440 d vs. 1125 d). In contrast, patients carrying a Flt3‐ITD mutation had a significant worse overall survival compared to wildtype patients ( = 0.03, median 210 d for group 3 + 4 vs. 634 d for group 1 + 2) while no difference of CR rate could be observed (42.8% vs. 48.9%,  = 0.91). As elderly but medically fit patients with AML carrying a NPM1 mutation have a high CR rate, age itself should not be a barrier for induction treatment. However, new therapeutic concepts of postremission therapy (e.g. allogeneic stem cell transplantation after dose‐reduced conditioning) should be considered for these patients in first CR.
    Keywords: Aml ; Npm1 ; Flt3‐Itd ; Elderly Patients ; Prognosis
    ISSN: 0902-4441
    E-ISSN: 1600-0609
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  • 6
    Language: English
    In: Annals of Hematology, 2007, Vol.86(10), pp.763-765
    Description: Byline: Sebastian Scholl (1), Joachim Luftner (2), Lars-Olof Mugge (1), Volker Schmidt (1), Hans-Jorg Fricke (1), Klaus Hoffken (1) Author Affiliation: (1) Department of Internal Medicine II (Oncology/Hematology/Gastroenterology/Infectious Disease), Medical Faculty at Friedrich Schiller University, Erlanger Allee 101, 07740, Jena, Germany (2) Institute of Pathology, Meiningen, Germany Article History: Registration Date: 25/05/2007 Received Date: 17/12/2006 Accepted Date: 02/01/2007 Online Date: 17/07/2007
    Keywords: Sarcoma -- Diagnosis ; Sarcoma -- Genetic Aspects;
    ISSN: 0939-5555
    E-ISSN: 1432-0584
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