Prognostic impact of a suboptimal number of analyzed metaphases in normal karyotype lower-risk MDS

Conventional karyotype is one of the most relevant prognostic factors in MDS. However, about 50% of patients with MDS have a normal karyotype. Usually, 20-25 normal metaphases (nMP) are considered to be optimal to exclude small abnormal clones which might be associated with poor prognosis. This study evaluated the impact of examining a suboptimal number of metaphases in patients recruited to the EUMDS Registry with low and intermediate-1 risk according to IPSS. Only 179/1049 (17%) of patients with a normal karyotype had a suboptimal number of nMP, defined as less than 20 metaphases analyzed. The outcome (overall survival and progression-free survival) of patients with suboptimal nMP was not inferior to those with higher numbers of analyzed MP both in univariate and multivariate analyses. For patients with an abnormal karyotype, 224/649 (35%) had a suboptimal number of MP assessed, but this did not impact on outcome. For patients with a normal karyotype and suboptimal numbers of analyzable metaphases standard evaluation might be acceptable for general practice, but we recommend additional FISH-analyses or molecular techniques, especially in candidates for intensive interventions

p53-binding protein 1 is fused to the platelet-derived growth factor receptor ? in a patient with a t(5;15)(q33;q22) and an imatinib-responsive eosinophilic myeloproliferative disorder

We describe the fusion of TP53BP1 to PDGFRB in a patient with a chronic myeloid leukemia-like disorder associated with eosinophilia and a t(5;15)(q33;q22). TP53BP1 encodes 53BP1, a p53-binding protein that plays a role in cellular responses to DNA damage. The 53BP1-PDGFRß fusion protein is predicted to retain the kinetochore-binding domain of 53BP1 fused to the transmembrane and intracellular tyrosine kinase domain of PDGFRß. The presence of the fusion was confirmed by two-color fluorescence in situ hybridization, reverse transcription-PCR, and by characterizing the genomic breakpoints. The reciprocal fusion, which would contain the p53-binding 53BP1 BRCA1 COOH-terminal domains, was not detectable by fluorescence in situ hybridization or nested PCR. Imatinib, a known inhibitor of PDGFRß, blocked the growth of patient colony-forming unit, granulocyte-macrophage in vitro and produced a clinically significant response before relapse and subsequent death with imatinib-resistant disease. We conclude that TP53BP1-PDGFRB is a novel imatinib target in atypical chronic myeloid leukemia. <br/

Overexpression of the proneural transcription factor ASCL1 in chronic lymphocytic leukemia with a t(12;14)(q23.2;q32.3)

Abstract Background Translocations of the IGH locus on 14q32.3 are present in about 8% of patients with chronic lymphocytic leukemia (CLL) and contribute to leukemogenesis by deregulating the expression of the IGH-partner genes. Identification of these genes and investigation of the downstream effects of their deregulation can reveal disease-causing mechanisms. Case presentation We report on the molecular characterization of a novel t(12;14)(q23.2;q32.3) in CLL. As a consequence of the rearrangement ASCL1 was brought into proximity of the IGHJ-Cμ enhancer and was highly overexpressed in the aberrant B-cells of the patient, as shown by qPCR and immunohistochemistry. ASCL1 encodes for a transcription factor acting as a master regulator of neurogenesis, is overexpressed in neuroendocrine tumors and a promising therapeutic target in small cell lung cancer (SCLC). Its overexpression has also been recently reported in acute adult T-cell leukemia/lymphoma. To examine possible downstream effects of the ASCL1 upregulation in CLL, we compared the gene expression of sorted CD5+ cells of the translocation patient to that of CD19+ B-cells from seven healthy donors and detected 176 significantly deregulated genes (Fold Change ≥2, FDR p ≤ 0.01). Deregulation of 55 genes in our gene set was concordant with at least two studies comparing gene expression of normal and CLL B-lymphocytes. INSM1, a well-established ASCL1 target in the nervous system and SCLC, was the gene with the strongest upregulation (Fold Change = 209.4, FDR p = 1.37E-4). INSM1 encodes for a transcriptional repressor with extranuclear functions, implicated in neuroendocrine differentiation and overexpressed in the majority of neuroendocrine tumors. It was previously shown to be induced in CLL cells but not in normal B-cells upon treatment with IL-4 and to be overexpressed in CLL cells with unmutated versus mutated IGHV genes. Its role in CLL is still unexplored. Conclusion We identified ASCL1 as a novel IGH-partner gene in CLL. The neural transcription factor was strongly overexpressed in the patient’s CLL cells. Microarray gene expression analysis revealed the strong upregulation of INSM1, a prominent ASCL1 target, which was previously shown to be induced in CLL cells upon IL-4 treatment. We propose further investigation of the expression and potential role of INSM1 in CLL

Ixazomib in combination with carboplatin in pretreated women with advanced triple-negative breast cancer, a phase I/II trial of the AGMT (AGMT MBC-10 trial)

Abstract Background Triple-negative breast cancer (TNBC) comprises a heterogeneous group of diseases which are generally associated with poor prognosis. Up to now, no targeted treatment beyond anti-VEGF therapy has been approved for TNBC and cytotoxic agents remain the mainstay of treatment. Ixazomib is a selective and reversible inhibitor of the proteasome, which has been mainly investigated in the treatment of multiple myeloma. In a preclinical study TNBC cells were treated with the first-generation proteasome inhibitor bortezomib in combination with cisplatin and synergistic efficacy was demonstrated. Clinical data are available for carboplatin plus bortezomib in metastatic ovarian and lung cancers showing remarkable antitumor activity and good tolerability (Mol Cancer 11:26 2012, J Thorac Oncol 4:87–92 2009, J Thorac Oncol 7:1032–1040, 2012). Based on this evidence, the phase I/II MBC-10 trial will evaluate the toxicity profile and efficacy of the second-generation proteasome inhibitor ixazomib in combination with carboplatin in patients with advanced TNBC. Methods Patients with metastatic TNBC pretreated with at least one prior line of chemotherapy for advanced disease with a confirmed disease progression and measurable disease according to RECIST criteria 1.1 are eligible for this study. Patients will receive ixazomib in combination with carboplatin on days 1, 8, and 15 in a 28-day cycle. The phase I part of this study utilizes an alternate dose escalation accelerated titration design. After establishing the maximum tolerated dose (MTD), the efficacy and safety of the combination will be further evaluated (phase II, including 41 evaluable patients). All patients will continue on study drugs until disease progression, unacceptable toxicity or discontinuation for any other reason. Primary endpoint of the phase II is overall response rate, secondary endpoints include progression-free survival, safety, and quality of life. This trial is open for patient enrollment since November 2016 in six Austrian cancer centers. Accrual is planned to be completed within 2 years. Discussion Based on preclinical and clinical findings an ixazomib and carboplatin combination is thought to be effective in metastatic TNBC patients. The MBC-10 trial is accompanied by a broad biomarker program investigating predictive biomarkers for treatment response and potential resistance mechanisms to the investigational drug combination. Trial registration EudraCT Number: 2016–001421-13 received on March 31, 2016, ClinicalTrials.gov Identifier: NCT02993094 first posted on December 15, 2016. This trial was registered prospectively