Inhibition of lysyl oxidases synergizes with 5-azacytidine to restore erythropoiesis in myelodysplastic and myeloid malignancies

Limited response rates and frequent relapses during standard of care with hypomethylating agents in myelodysplastic neoplasms (MN) require urgent improvement of this treatment indication. Here, by combining 5-azacytidine (5-AZA) with the pan-lysyl oxidase inhibitor PXS-5505, we demonstrate superior restoration of erythroid differentiation in hematopoietic stem and progenitor cells (HSPCs) of MN patients in 20/31 cases (65%) versus 9/31 cases (29%) treated with 5-AZA alone. This effect requires direct contact of HSPCs with bone marrow stroma components and is dependent on integrin signaling. We further confirm these results in vivo using a bone marrow niche-dependent MN xenograft model in female NSG mice, in which we additionally demonstrate an enforced reduction of dominant clones as well as significant attenuation of disease expansion and normalization of spleen sizes. Overall, these results lay out a strong pre-clinical rationale for efficacy of combination treatment of 5-AZA with PXS-5505 especially for anemic MN

Impact of centralized evaluation of bone marrow histology in systemic mastocytosis

BACKGROUND:Bone marrow (BM) histology/immunohistochemistry, KIT D816V mutation analysis and serum tryptase measurements are mandatory tools for diagnosis of systemic mastocytosis (SM).MATERIALS AND METHODS: Within the 'German Registry of Disorders on Eosinophils and Mast Cells', we identified 65 SM patients who had two consecutive BM biopsies. The first biopsy was evaluated by a local pathologist (LP), the second biopsy by a reference pathologist (RP) of the 'European Competence Network on Mastocytosis (ECNM)'.RESULTS: Final diagnoses by RP were SM (n = 27), SM or aggressive SM (ASM) with associated non-mast cell lineage hematologic disease [(A)SM-AHNMD, n = 34)] or mast cell leukemia ± AHNMD (n = 4). In 15/65 patients (23%), initial diagnoses by LP were incorrect (by overlooking SM), e.g. primary myelofibrosis (n = 3), myelodysplastic/myeloproliferative neoplasm unclassified (n = 3), B-cell lymphoma (n = 2). Fourteen of 15 patients (93%) with incorrect diagnosis had an advanced SM, mostly (A)SM-AHNMD. In the 50 concordantly diagnosed patients, immunohistochemical markers for quantitative assessment of mast cell infiltration, e.g. CD117 (KIT) or CD25, were applied by LP in only 34/50 patients (68%), and mutational analysis for KIT D816V was performed or recommended in only 13/50 patients (26%). Finally, the subclassification of SM was discordant because LP did not diagnose AHNMD in 9/50 (18%) patients.CONCLUSIONS: In summary, adequate diagnosis and subclassification of SM requires an in-depth evaluation of the BM by experienced hematopathologists (preferably in a reference center) in combination with molecular genetics, serum tryptase and clinical parameters

The soluble transferrin receptor (TfR)-F-Index is not applicable as a test for iron status in patients with chronic lymphocytic leukemia

Background: The soluble transferrin receptor (sTfR) is established as a test for iron deficiency (ID). In chronic lymphocytic leukemia (CLL), sTfR is not reliable for screening for ID as the latter is strongly dependent on tumor burden. Methods: We investigated whether the influence of the tumor load can be excluded or minimized using the sTfR/log ferritin ratio (TfR-F-Index) and the C-reactive protein (CRP)-adjusted TfR-F-Index in 87 patients with CLL. sTfR was measured nephelometrically (normal: 0.81–1.75 mg/L). A cut-off value of 1.5 for the TfR-F-Index and 0.8 for the CRP-adjusted TfR-F-Index, in patients with a CRP >5 mg/L, was used. Results: All Binet A patients had normal sTfR values (1.34±0.2 mg/L), TfR-F-Index (0.67±0.2) and a CRP-adjusted TfR-F-Index. In Binet B and C, sTfR and the TfR-F-Index were significantly increased compared to Binet A patients (p<0.0001). The differences between Binet B and C were not significant. sTfR was increased in 85%, TfR-F-Index in 46% and the CRP-adjusted TfR-F-Index in 54% of the Binet B patients, in Binet C patients, 80%, 50% and 60% showed increases, respectively. sTfR and the TfR-F-Index decreased or even normalized following successful treatment. Conclusions: Similar to sTfR, the TfR-F-Index is strongly associated with tumor burden in patients with CLL. Thus, these parameters do not allow for a reliable diagnosis of ID in this patient group. Clin Chem Lab Med 2009;47:1291–5.Peer Reviewe

Eisenmangel und Eisenmangelanämie

Eisenmangel ist definiert als Verminderung des Gesamtkörpereisens. Eine Eisenmangelanämie liegt vor, wenn die Hämoglobinkonzentration eisenmangelbedingt unter den alters-, bzw. geschlechtsspezifischen Normwert absinkt. Dieser beträgt nach WHO 12 g/dl für Frauen und 13 g/dl für Männer

Response of ETV6-FLT3 positive myeloid/lymphoid neoplasm with eosinophilia to inhibitors of FMS-like tyrosine kinase 3

Imatinib-resistant tyrosine kinase (TK) fusions involving FGFR1, JAK2, or FLT3 are rare but recurrent in patients with eosinophilia-associated neoplasms. We report here 2 male patients with ETV6-FLT3+ myeloid/lymphoid neoplasms with eosinophilia who were treated with the multitargeted TK inhibitors sunitinib and sorafenib. Patient 1 achieved rapid complete hematologic response and complete cytogenetic response after 3 months of taking sunitinib. A secondary blast phase caused by clonal evolution was diagnosed after 6 months. He achieved a second complete hematologic response after taking sorafenib but relapsed 2 months later. An N841K point mutation within the TK domain of FLT3, previously reported in acute myeloid leukemia and potentially conferring resistance to sorafenib, was subsequently identified. Patient 2 was heavily pretreated according to the initial diagnosis of T-lymphoblastic lymphoma and died in sunitinib-induced pancytopenia. This report highlights the importance of a careful diagnostic workup for eosinophilia-associated neoplasms to evaluate the possibility of TK inhibitor therapy. <br/