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Friederike Schneider,
Eva Hoster,
Stephanie Schneider,
Annika Dufour,
Tobias Benthaus,
Purvi M Kakadia,
Stefan K Bohlander,
Jan Braess,
Achim Heinecke,
Maria C Sauerland, [......],
Bernhard J Woermann,
Michaela Feuring-Buske,
Christian Buske,
Ursula Creutzig,
Christian Thiede,
Michel C Zwaan,
Marry M van den Heuvel-Eibrink,
Dirk Reinhardt,
Wolfgang Hiddemann,
Karsten Spiekermann
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ABSTRACT: Prognosis of AML in elderly patients is poor due to adverse patient characteristics and comorbidities. In addition, disease-associated parameters reveal differences between older and younger patients with AML. Survival in normal karyotype AML (NK-AML) is influenced by different clinical and molecular markers. The aim of this work was to investigate the frequencies of molecular markers in patients with NK-AML with a focus on NPM1 mutations and FLT3-ITD in different age groups. In the present study, we analyzed the frequencies of mutations of NPM1 and FLT3-ITD in a cohort of 1,321 adult patients and 148 children with AML treated within the AMLCG99, the AML98, and AML04 trials and their distribution in different age groups. Additionally, the frequencies of mutations in CEBPA genes, FLT3-TKD, and MLL-PTD were analyzed in the cohort with NK-AML (n = 729). Our data show that the presence of mutations of NPM1 (from 60% to 40%) and FLT3-ITD (from 50% to 20%) significantly decreased with age in adult AML. Consequently, the proportion of NPM1-/FLT3-ITD- patients increased with age. The decreasing frequency of NPM1 mutations in elderly patients was paralleled by a reduced complete remission (CR) rate in the elderly of 55% compared to 80% in the younger patients. By contrast, the frequencies of other gene mutations, like FLT3-TKD and MLL-PTD, and mutations in CEBPA were not age-dependent. The decreasing frequency of the favorable NPM1 mutations with increasing age may partially explain the worse outcome in the elderly patients. Furthermore, the increasing amount of elderly patients without NPM1 mutations or FLT3-ITD suggests that other molecular and clinical risk factors may influence prognosis in this age group.
Annals of Hematology 07/2011; 91(1):9-18. · 2.62 Impact Factor
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Friederike Schneider,
Eva Hoster,
Michael Unterhalt,
Stephanie Schneider,
Annika Dufour,
Tobias Benthaus,
Gudrun Mellert,
Evelin Zellmeier,
Stefan K Bohlander,
Michaela Feuring-Buske,
Christian Buske,
Jan Braess,
Susanne Fritsch,
Achim Heinecke,
Maria C Sauerland,
Wolfgang E Berdel, Thomas Buechner,
Bernhard J Woermann,
Wolfgang Hiddemann,
Karsten Spiekermann
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ABSTRACT: Mutations in the NPM1 gene represent the most frequent genetic alterations in patients with acute myeloid leukemia (AML) and are associated with a favorable outcome. In 690 normal karyotype (NK) AML patients the complete remission rates (CRs) and the percentage of patients with adequate in vivo blast cell reduction 1 week after the end of the first induction cycle were significantly higher in NPM1(+) (75% and 80%, respectively) than in NPM1(-) (57% and 57%, respectively) patients, but were unaffected by the FLT3-ITD status. Multivariate analyses revealed the presence of a NPM1 mutation as an independent positive prognostic factor for the achievement of an adequate day-16 blast clearance and a CR. In conclusion, NPM1(+) blast cells show a high in vivo sensitivity toward induction chemotherapy irrespective of the FLT3-ITD mutation status. These findings provide insight into the pathophysiology and help to understand the favorable clinical outcome of patients with NPM1(+) AML.
Blood 04/2009; 113(21):5250-3. · 9.90 Impact Factor
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ABSTRACT: Vascular endothelial growth factor-C (VEGF-C) has been shown to promote survival and resistance to chemotherapy of AML-cells in vitro. We investigated the expression of VEGF-C/VEGFR-3 in the bone marrow and pretherapeutic plasma levels of VEGF-C in patients with newly diagnosed AML. Expression of VEGF-C/VEGFR-3 was significantly higher in AML patients than in controls, while circulating levels did not differ. However, VEGF-C/VEGFR-3 expression was not able to predict clinical outcome. In conclusion, AML is associated with an increased expression of VEGF-C/VEGFR-3. Although expression levels display no prognostic significance in our study, strategies targeting the VEGF-C/VEGFR-3-pathway might be a promising treatment approach.
Leukemia Research 07/2008; 32(6):954-61. · 2.92 Impact Factor
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ABSTRACT: Neuropilin-1 (NRP-1), a non-tyrosine kinase receptor functioning as a mediator of angiogenesis and neuronal guidance, was recently found to be significantly overexpressed in newly diagnosed acute myeloid leukemia (AML) patients with significant correlation to survival. The role of NRP-1 in refractory or relapsed AML patients and its regulation during anti-angiogenic treatment remain to be elucidated.
Bone marrow biopsies of 10 patients with refractory or relapsed AML were evaluated for NRP-1 expression by immunohistochemical analysis, and NRP-1 expression level was determined before and after start of thalidomide therapy and correlated to response and growth factor expression.
NRP-1 expression was significantly increased in AML patients [median 7 arbitrary units (AU)] when compared with controls (n = 38, median 2.75 AU). Under thalidomide treatment, a marked difference in the course of NRP-1 expression between responders and non-responders was observed, however, without a statistical significance (P = 0.071) being reached. Additionally, a significant correlation of the NRP-1 expression level to microvessel density could be detected under treatment with thalidomide (P = 0.018).
Our data provide evidence of increased NRP-1 expression in relapsed or refractory AML. Additionally, our results suggest that thalidomide-induced antileukemic properties might at least in part be mediated by NRP-1 downregulation.
European Journal Of Haematology 12/2007; 79(5):392-7. · 2.61 Impact Factor
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Thomas Buechner,
Wolfgang E Berdel,
Claudia Schoch,
Torsten Haferlach,
Hubert L Serve,
Susanne Schnittger,
Wolfgang Kern,
Joelle Tchinda,
Albrecht Reichle,
Peter Staib,
Wolf-Dieter Ludwig,
Carlo Aul,
Maria-Cristina Sauerland,
Achim Heinecke,
Bernhard Woermann,
Wolfgang Hiddemann
Hematology 02/2005; 10 Suppl 1:281-85. · 1.49 Impact Factor
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ABSTRACT: Emerging data suggest an involvement of angiogenesis in the pathophysiology of acute myeloid leukemia (AML). Thus, antiangiogenic therapy could constitute a novel strategy for the treatment of AML. To test this hypothesis, a phase I/II dose-escalating trial was performed to study the safety and efficacy of thalidomide, a putative inhibitor of angiogenesis, in 20 patients with AML. Thirteen patients were assessable for both toxicity and response, tolerating a maximum dose of 200 to 400 mg daily for at least 1 month. Seven patients had to be prematurely withdrawn from drug administration owing to progressive disease and death (3 patients), personal decision (2 patients), or inability to tolerate thalidomide (2 patients). Overall, adverse events were fatigue, constipation, rash, and neuropathy (grade 1 to 2 in most patients). In 4 patients, a partial response, defined as reduction of at least 50% in the blast cell infiltration of the bone marrow accompanied by increases in platelet counts and hemoglobin values, was observed. One additional patient showed a hematologic improvement without fulfilling the criteria of a partial response. The responses lasted a median of 3 months (range, 1-8 months). In parallel, microvessel densities significantly decreased in these 5 patients during treatment with thalidomide (P <.05). This decrease was accompanied by declining plasma levels of basic fibroblast growth factor, one of the most potent angiogenic growth factors. In conclusion, single-agent thalidomide has antiangiogenic and antileukemic activity in AML, although a causal relationship between both effects has still to be proven.
Blood 03/2002; 99(3):834-9. · 9.90 Impact Factor
