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Andrew W Roberts - One of the best experts on this subject based on the ideXlab platform.

  • efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables
    Blood, 2019
    Co-Authors: Andrew W Roberts, Barbara Eichhorst, Thomas J Kipps, Steven Coutre, Matthew S Davids, Michael Hallek, John C Byrd, Kathryn Humphrey, Lang Zhou, Brenda Chyla
    Abstract:

    To define the efficacy of venetoclax with extended follow-up and identify clinical or biological treatment effect modifiers, updated data for previously treated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) enrolled in 4 early-phase trials were pooled. Rates of response, complete remission (CR/CRi), and undetectable minimal residual disease (U-MRD) were analyzed for all patients (n = 436) and for those patients who were planned to receive 400 mg/day monotherapy (n = 347). Univariate and multiple regression analyses were performed to identify the pretreatment factors associated with response rates and duration of response (DoR). Objective responses were documented in 75% of all patients, including 22% CR/CRi. Overall, 27% and 16% of the patients achieved U-MRD in blood and marrow, respectively. Estimated median progression-free survival (PFS), DoR, and time to progression were 30.2, 38.4, and 36.9 months, respectively. Similar efficacy outcomes were observed within the 400 mg/day monotherapy subset. For those who achieved CR/CRi, the 3-year PFS estimate was 83%. DoR was superior for patients achieving CR/CRi or U-MRD in landmark analyses. In multiple regression analyses, bulky lymphadenopathy (≥5 cm) and refractoriness to B-cell receptor inhibitor (BCRi) therapy were significantly associated with lower CR rate and shorter DoR. Fewer prior therapies were associated with higher CR rate, but not DoR. Chromosome 17p deletion and/or TP53 mutation and NOTCH1 mutation were consistently associated with shorter DoR, but not probability of response. Thus, both pretreatment factors and depth of response correlated with DoR with venetoclax. Patients without bulky lymphadenopathy, BCRi-refractory CLL, or an adverse mutation profile had the most durable benefit.

  • comprehensive safety analysis of venetoclax monotherapy for patients with relapsed refractory chronic lymphocytic leukemia
    Clinical Cancer Research, 2018
    Co-Authors: Matthew S Davids, Su Young Kim, Andrew W Roberts, Michael Hallek, William G Wierda, Stephan Stilgenbauer, Jeffrey A Jones, John F Gerecitano, Jalaja Potluri, Todd Busman
    Abstract:

    Purpose: The oral BCL-2 inhibitor venetoclax is an effective therapy for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), including disease with high-risk genomic features such as Chromosome 17p deletion [del(17p)] or progressive disease following B-cell receptor pathway inhibitors.Patients and Methods: We conducted a comprehensive analysis of the safety of 400 mg daily venetoclax monotherapy in 350 patients with CLL using an integrated dataset from three phase I/II studies.Results: Median age was 66 years and 60% had del(17p). Patients had received a median of three prior therapies (range: 0-15); 42% previously received ibrutinib or idelalisib. Median duration of exposure to venetoclax was 16 months (0-56). In the pooled analysis, the most common adverse events (AE) of any grade were diarrhea (41%), neutropenia (40%), nausea (39%), anemia (31%), fatigue (28%), and upper respiratory tract infection (25%). The most common grade 3/4 AEs were neutropenia (37%), anemia (17%), and thrombocytopenia (14%). With the current 5-week ramp-up dosing, the incidence of laboratory TLS was 1.4% (2/166), none had clinical sequelae, and all of these patients were able to ramp-up to a daily dose of 400 mg. Grade 3/4 neutropenia was manageable with growth factor support and dose adjustments; the incidence of serious infections in these patients was 15%. Ten percent of patients discontinued venetoclax due to AEs and 8% died while on study, with the majority of deaths in the setting of disease progression.Conclusions: Venetoclax as a long-term continuous therapy is generally well tolerated in patients with R/R CLL when initiated with the current treatment algorithm. Clin Cancer Res; 24(18); 4371-9. ©2018 AACR.

  • venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion a multicentre open label phase 2 study
    Lancet Oncology, 2016
    Co-Authors: Stephan Stilgenbauer, Barbara Eichhorst, John F Seymour, Andrew W Roberts, Steven Coutre, Soham D Puvvada, Johannes Schetelig, Talha Munir, Clemens M Wendtner, Wojciech Jurczak
    Abstract:

    Summary Background Deletion of Chromosome 17p (del[17p]) in patients with chronic lymphocytic leukaemia confers very poor prognosis when treated with standard chemo-immunotherapy. Venetoclax is an oral small-molecule BCL2 inhibitor that induces chronic lymphocytic leukaemia cell apoptosis. In a previous first-in-human study of venetoclax, 77% of patients with relapsed or refractory chronic lymphocytic leukaemia achieved an overall response. Here we aimed to assess the activity and safety of venetoclax monotherapy in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia. Methods In this phase 2, single-arm, multicentre study, we recruited patients aged 18 years and older with del(17p) relapsed or refractory chronic lymphocytic leukaemia (as defined by 2008 Modified International Workshop on Chronic Lymphocytic Leukemia guidelines) from 31 centres in the USA, Canada, UK, Germany, Poland, and Australia. Patients started once daily venetoclax with a weekly dose ramp-up schedule (20, 50, 100, 200, 400 mg) over 4–5 weeks. Patients were then given daily 400 mg continuous dosing until disease progression or discontinuation for another reason. The primary endpoint was the proportion of patients achieving an overall response, assessed by an independent review committee. Activity and safety analyses included all patients who received at least one dose of study drug (per protocol). This study is registered with ClinicalTrials.gov, number NCT01889186. Follow-up is ongoing, and patients are still receiving treatment. Findings Between May 27, 2013, and June 27, 2014, 107 patients were enrolled into the study. At a median follow-up of 12·1 months (IQR 10·1–14·2), an overall response by independent review was achieved in 85 (79·4%; 95% CI 70·5–86·6) of 107 patients. The most common grade 3–4 adverse events were neutropenia (43 [40%]), infection (21 [20%]), anaemia (19 [18%]), and thrombocytopenia (16 [15%]). Serious adverse events occurred in 59 (55%) patients, irrespective of their relationship to treatment, with the most common (≥5% of patients) being pyrexia and autoimmune haemolytic anaemia (seven [7%] each), pneumonia (six [6%]), and febrile neutropenia (five [5%]). 11 patients died in the study within 30 days of the last dose of venetoclax; seven due to disease progression and four from an adverse event (none assessed as treatment related). Interpretation Results of this trial show that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia, providing a new therapeutic option for this very poor prognosis population. Additionally, in view of the distinct mechanism-of-action of venetoclax, combinations or sequencing with other novel targeted agents should be investigated to further advance treatment of del(17p) chronic lymphocytic leukaemia. Funding AbbVie and Genentech.

  • targeting bcl2 with venetoclax in relapsed chronic lymphocytic leukemia
    The New England Journal of Medicine, 2016
    Co-Authors: Andrew W Roberts, Mary Ann Anderson, Thomas J Kipps, Matthew S Davids, John F Gerecitano, John M Pagel, Brad S Kahl, Soham D Puvvada, Jennifer R Brown
    Abstract:

    BACKGROUND New treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets BCL2, a protein central to the survival of CLL cells. METHODS We conducted a phase 1 dose-escalation study of daily oral venetoclax in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile, and efficacy. In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In an expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day. RESULTS The majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects in cluded mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with Chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%. CONCLUSIONS Selective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. (Funded by AbbVie and Genentech; ClinicalTrials.gov number, NCT01328626.)

Birgitta Lannering - One of the best experts on this subject based on the ideXlab platform.

  • prognostic effect of whole chromosomal aberration signatures in standard risk non wnt non shh medulloblastoma a retrospective molecular analysis of the hit siop pnet 4 trial
    Lancet Oncology, 2018
    Co-Authors: Tobias Goschzik, Anja Zur Muehlen, Stefan Rutkowski, Edward C Schwalbe, Debbie Hicks, Amanda Smith, Dominique Figarellabranger, Francois Doz, Birgitta Lannering
    Abstract:

    Summary Background Most children with medulloblastoma fall within the standard-risk clinical disease group defined by absence of high-risk features (metastatic disease, large-cell/anaplastic histology, and MYC amplification), which includes 50–60% of patients and has a 5-year event-free survival of 75–85%. Within standard-risk medulloblastoma, patients in the WNT subgroup are established as having a favourable prognosis; however, outcome prediction for the remaining majority of patients is imprecise. We sought to identify novel prognostic biomarkers to enable improved risk-adapted therapies. Methods The HIT-SIOP PNET 4 trial recruited 338 patients aged 4–21 years with medulloblastoma between Jan 1, 2001, and Dec 31, 2006, in 120 treatment institutions in seven European countries to investigate hyperfractionated radiotherapy versus standard radiotherapy. In this retrospective analysis, we assessed the remaining tumour samples from patients in the HIT-SIOP PNET 4 trial (n=136). We assessed the clinical behaviour of the molecularly defined WNT and SHH subgroups, and identified novel independent prognostic markers and models for standard-risk patients with non-WNT/non-SHH disease. Because of the scarcity and low quality of available genomic material, we used a mass spectrometry-minimal methylation classifier assay (MS-MIMIC) to assess methylation subgroup and a molecular inversion probe array to detect genome-wide copy number aberrations. Prognostic biomarkers and models identified were validated in an independent, demographically matched cohort (n=70) of medulloblastoma patients with non-WNT/non-SHH standard-risk disease treated with conventional therapies (maximal surgical resection followed by adjuvant craniospinal irradiation [all patients] and chemotherapy [65 of 70 patients], at UK Children's Cancer and Leukaemia Group and European Society for Paediatric Oncology (SIOPE) associated treatment centres between 1990 and 2014. These samples were analysed by Illumina 450k DNA methylation microarray. HIT-SIOP PNET 4 is registered with ClinicalTrials.gov, number NCT01351870. Findings We analysed methylation subgroup, genome-wide copy number aberrations, and mutational features in 136 assessable tumour samples from the HIT-SIOP PNET 4 cohort, representing 40% of the 338 patients in the trial cohort. This cohort of 136 samples consisted of 28 (21%) classified as WNT, 17 (13%) as SHH, and 91 (67%) as non-WNT/non-SHH (we considered Group3 and Group4 medulloblastoma together in our analysis because of their similar molecular and clinical features). Favourable outcomes for WNT tumours were confirmed in patients younger than 16 years, and all relapse events in SHH (four [24%] of 17) occurred in patients with TP53 mutation ( TP53 mut ) or Chromosome 17p loss. A novel whole chromosomal aberration signature associated with increased ploidy and multiple non-random whole chromosomal aberrations was identified in 38 (42%) of the 91 samples from patients with non-WNT/non-SHH medulloblastoma in the HIT-SIOP PNET 4 cohort. Biomarkers associated with this whole chromosomal aberration signature (at least two of Chromosome 7 gain, Chromosome 8 loss, and Chromosome 11 loss) predicted favourable prognosis. Patients with non-WNT/non-SHH medulloblastoma could be reclassified by these markers as having favourable-risk or high-risk disease. In patients in the HIT-SIOP PNET4 cohort with non-WNT/non-SHH medulloblastoma, with a median follow-up of 6·7 years (IQR 5·8–8·2), 5-year event-free survival was 100% in the favourable-risk group and 68% (95% CI 57·5–82·7; p=0·00014) in the high-risk group. In the validation cohort, with a median follow-up of 5·6 years (IQR 3·1–8·1), 5-year event-free survival was 94·7% (95% CI 85·2–100) in the favourable-risk group and 58·6% (95% CI 45·1–76·1) in the high-risk group (hazard ratio 9·41, 95% CI 1·25–70·57; p=0·029). Our comprehensive molecular investigation identified subgroup-specific risk models which allowed 69 (51%) of 134 accessible patients from the standard-risk medulloblastoma HIT-SIOP PNET 4 cohort to be assigned to a favourable-risk group. Interpretation We define a whole chromosomal signature that allows the assignment of non-WNT/non-SHH medulloblastoma patients normally classified as standard-risk into favourable-risk and high-risk categories. In addition to patients younger than 16 years with WNT tumours, patients with non-WNT/non-SHH tumours with our defined whole chromosomal aberration signature and patients with SHH- TP53 wild-type tumours should be considered for therapy de-escalation in future biomarker-driven, risk-adapted clinical trials. The remaining subgroups of patients with high-risk medulloblastoma might benefit from more intensive therapies. Funding Cancer Research UK, Swedish Childhood Cancer Foundation, French Ministry of Health/French National Cancer Institute, and the German Children's Cancer Foundation.

  • biomarker driven stratification of disease risk in non metastatic medulloblastoma results from the multi center hit siop pnet4 clinical trial
    Oncotarget, 2015
    Co-Authors: Steven C Clifford, Tobias Goschzik, Edward C Schwalbe, Debbie Hicks, Dominique Figarellabranger, Birgitta Lannering, Kieran O Toole, Sarah Leigh Nicholson, Anja Zur Muhlen, Francois Doz
    Abstract:

    // Steven C. Clifford 1, * , Birgitta Lannering 2 , Ed C. Schwalbe 1, 3 , Debbie Hicks 1 , Kieran O' Toole 1 , Sarah Leigh Nicholson 1 , Tobias Goschzik 4 , Anja zur Muhlen 4 , Dominique Figarella-Branger 5 , Francois Doz 6 , Stefan Rutkowski 7 , Goran Gustafsson 8 , Torsten Pietsch 4, * , on behalf of the SIOP-Europe PNET Group 1 Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom 2 Department of Pediatrics, University of Gothenburg and The Queen Silvia Children's Hospital, Gothenburg, Sweden 3 Department of Applied Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom 4 Department of Neuropathology, University of Bonn, Bonn, Germany 5 Department of Pathology and Neuropathology, Assistance Publique Hopitaux de Marseille, Aix Marseille University, Marseille, France 6 Institut Curie and University Paris Descartes, Paris, France 7 University Medical Center Hamburg-Eppendorf, Hamburg, Germany 8 Karolinska Institute, Stockholm, Sweden * These authors have contributed equally to this work Correspondence to: Steven C. Clifford, e-mail: steve.clifford@ncl.ac.uk Keywords: medulloblastoma, clinical trial, biomarker, stratification Received: July 27, 2015      Accepted: August 24, 2015      Published: September 05, 2015 ABSTRACT Purpose: To improve stratification of risk-adapted treatment for non-metastatic (M0), standard-risk medulloblastoma patients by prospective evaluation of biomarkers of reported biological or prognostic significance, alongside clinico-pathological variables, within the multi-center HIT-SIOP-PNET4 trial. Methods: Formalin-fixed paraffin-embedded tumor tissues were collected from 338 M0 patients (>4.0 years at diagnosis) for pathology review and assessment of the WNT subgroup (MB WNT ) and genomic copy-number defects (Chromosome 17, MYC/MYCN , 9q22 ( PTCH1 ) and DNA ploidy). Clinical characteristics were reviewed centrally. Results: The favorable prognosis of MB WNT was confirmed, however better outcomes were observed for non-MB WNT tumors in this clinical risk-defined cohort compared to previous disease-wide clinical trials. Chromosome 17p/q defects were heterogeneous when assessed at the cellular copy-number level, and predicted poor prognosis when they occurred against a diploid (ch17(im)/diploid(cen)), but not polyploid, genetic background. These factors, together with post-surgical tumor residuum (R+) and radiotherapy delay, were supported as independent prognostic markers in multivariate testing. Notably, MYC and MYCN amplification were not associated with adverse outcome. In cross-validated survival models derived for the clinical standard-risk (M0/R0) disease group, (ch17(im)/diploid(cen); 14% of patients) predicted high disease-risk, while the outcomes of patients without (ch17(im)/diploid(cen)) did not differ significantly from MB WNT , allowing re-classification of 86% as favorable-risk. Conclusion: Biomarkers, established previously in disease-wide studies, behave differently in clinically-defined standard-risk disease. Distinct biomarkers are required to assess disease-risk in this group, and define improved risk-stratification models. Routine testing for specific patterns of Chromosome 17 imbalance at the cellular level, and MB WNT , provides a strong basis for incorporation into future trials.

Ma Jose Calasanz - One of the best experts on this subject based on the ideXlab platform.

  • karyotypic complexity rather than Chromosome 8 abnormalities aggravates the outcome of chronic lymphocytic leukemia patients with tp53 aberrations
    Oncotarget, 2016
    Co-Authors: Gonzalo Blanco, Panagiotis Baliakas, Anna Puiggros, Anastasia Athanasiadou, Madolores Garciamalo, Rosa Collado, Aliki Xochelli, Maria Rodriguezrivera, Margarita Ortega, Ma Jose Calasanz
    Abstract:

    // Gonzalo Blanco 1, 2, 3 , Anna Puiggros 1, 2 , Panagiotis Baliakas 4 , Anastasia Athanasiadou 5 , MaDolores Garcia-Malo 6 , Rosa Collado 7 , Aliki Xochelli 4, 8 , Maria Rodriguez-Rivera 1, 2 , Margarita Ortega 9 , Ma Jose Calasanz 10 , Elisa Luno 11 , MaTeresa Vargas 12 , Javier Grau 13 , Carolina Martinez-Laperche 14 , Alberto Valiente 15 , Jose Cervera 16 , Achilles Anagnostopoulos 5 , Eva Gimeno 17 , Eugenia Abella 17 , Evangelia Stalika 8 , Jesus Ma Hernandez-Rivas 18 , Francisco Jose Ortuno 6 , Diego Robles 19 , Ana Ferrer 1, 2 , David Ivars 7 , Marcos Gonzalez 18 , Francesc Bosch 9 , Pau Abrisqueta 9 , Kostas Stamatopoulos 4, 5, 8 , Blanca Espinet 1, 2 1 Laboratori de Citogenetica Molecular, Laboratori de Citologia Hematologica, Servei de Patologia, Hospital del Mar, Barcelona, Spain 2 Grup de Recerca Translacional en Neoplasies Hematologiques, Cancer Research Programme, IMIM-Hospital del Mar, Barcelona, Spain 3 Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain 4 Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden 5 Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece 6 Servicio de Hematologia, Hospital Universitario Morales Meseguer, Murcia, Spain 7 Servicio de Hematologia, Consorcio Hospital General Universitario, Valencia, Spain 8 Institute of Applied Biosciences, CERTH, Thessaloniki, Greece 9 Laboratorio de Citogenetica y Servicio de Hematologia, Hospital Vall d'Hebron, Barcelona, Spain 10 Servicio de Citogenetica, Departamento de Genetica, Universidad de Navarra, Pamplona, Spain 11 Servicio de Hematologia, Hospital Universitario Central de Asturias, Oviedo, Spain 12 UGC de Hematologia, Hospital Universitario Virgen del Rocio, Instituto de Biomedicina de Sevilla (IBIS), Sevilla, Spain 13 Servei d’Hematologia, ICO-Hospital Germans Trias i Pujol, Institut de Recerca Contra la Leucemia Josep Carreras (IJC), Universitat Autonoma de Barcelona, Badalona, Spain 14 Laboratorio de Genetica Hematologica, Servicio de Hematologia, Hospital G.U. Gregorio Maranon, Instituto de Investigacion Sanitaria Gregorio Maranon, Madrid, Spain 15 Servicios de Genetica y Hematologia, Complejo Hospitalario de Navarra, Pamplona, Spain 16 Unidad de Genetica, Hospital Universitario La Fe, Valencia, Spain 17 Servei d’Hematologia, Hospital del Mar, Barcelona, Spain 18 Servicio de Hematologia, Hospital Universitario de Salamanca, IBSAL, IBMCC, Centro de Investigacion del Cancer, Universidad de Salamanca, CSIC, Salamanca, Spain 19 Servicio de Hematologia, Hospital Txagorritxu, Vitoria, Spain Correspondence to: Blanca Espinet, email: bespinet@parcdesalutmar.cat Keywords: CLL, TP53 aberrations, Chromosome 8 abnormalities, complex karyotype, prognosis Received: August 02, 2016      Accepted: October 27, 2016      Published: November 04, 2016 ABSTRACT Patients with chronic lymphocytic leukemia (CLL) harboring TP53 aberrations ( TP53 abs; Chromosome 17p deletion and/or TP53 mutation) exhibit an unfavorable clinical outcome. Chromosome 8 abnormalities, namely losses of 8p (8p−) and gains of 8q (8q+) have been suggested to aggravate the outcome of patients with TP53 abs. However, the reported series were small, thus hindering definitive conclusions. To gain insight into this issue, we assessed a series of 101 CLL patients harboring TP53 disruption. The frequency of 8p− and 8q+ was 14.7% and 17.8% respectively. Both were associated with a significantly ( P < 0.05) higher incidence of a complex karyotype (CK, ≥3 abnormalities) detected by Chromosome banding analysis (CBA) compared to cases with normal 8p (N-8p) and 8q (N-8q), respectively. In univariate analysis for 10-year overall survival (OS), 8p− ( P = 0.002), 8q+ ( P = 0.012) and CK ( P = 0.009) were associated with shorter OS. However, in multivariate analysis only CK (HR = 2.47, P = 0.027) maintained independent significance, being associated with a dismal outcome regardless of Chromosome 8 abnormalities. In conclusion, our results highlight the association of Chromosome 8 abnormalities with CK amongst CLL patients with TP53 abs, while also revealing that CK can further aggravate the prognosis of this aggressive subgroup.

  • karyotypic complexity rather than Chromosome 8 abnormalities aggravates the outcome of chronic lymphocytic leukemia patients with tp53 aberrations
    Oncotarget, 2016
    Co-Authors: Gonzalo Blanco, Panagiotis Baliakas, Anna Puiggros, Anastasia Athanasiadou, Madolores Garciamalo, Rosa Collado, Aliki Xochelli, Maria Rodriguezrivera, Margarita Ortega, Ma Jose Calasanz
    Abstract:

    // Gonzalo Blanco 1, 2, 3 , Anna Puiggros 1, 2 , Panagiotis Baliakas 4 , Anastasia Athanasiadou 5 , MaDolores Garcia-Malo 6 , Rosa Collado 7 , Aliki Xochelli 4, 8 , Maria Rodriguez-Rivera 1, 2 , Margarita Ortega 9 , Ma Jose Calasanz 10 , Elisa Luno 11 , MaTeresa Vargas 12 , Javier Grau 13 , Carolina Martinez-Laperche 14 , Alberto Valiente 15 , Jose Cervera 16 , Achilles Anagnostopoulos 5 , Eva Gimeno 17 , Eugenia Abella 17 , Evangelia Stalika 8 , Jesus Ma Hernandez-Rivas 18 , Francisco Jose Ortuno 6 , Diego Robles 19 , Ana Ferrer 1, 2 , David Ivars 7 , Marcos Gonzalez 18 , Francesc Bosch 9 , Pau Abrisqueta 9 , Kostas Stamatopoulos 4, 5, 8 , Blanca Espinet 1, 2 1 Laboratori de Citogenetica Molecular, Laboratori de Citologia Hematologica, Servei de Patologia, Hospital del Mar, Barcelona, Spain 2 Grup de Recerca Translacional en Neoplasies Hematologiques, Cancer Research Programme, IMIM-Hospital del Mar, Barcelona, Spain 3 Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain 4 Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden 5 Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece 6 Servicio de Hematologia, Hospital Universitario Morales Meseguer, Murcia, Spain 7 Servicio de Hematologia, Consorcio Hospital General Universitario, Valencia, Spain 8 Institute of Applied Biosciences, CERTH, Thessaloniki, Greece 9 Laboratorio de Citogenetica y Servicio de Hematologia, Hospital Vall d'Hebron, Barcelona, Spain 10 Servicio de Citogenetica, Departamento de Genetica, Universidad de Navarra, Pamplona, Spain 11 Servicio de Hematologia, Hospital Universitario Central de Asturias, Oviedo, Spain 12 UGC de Hematologia, Hospital Universitario Virgen del Rocio, Instituto de Biomedicina de Sevilla (IBIS), Sevilla, Spain 13 Servei d’Hematologia, ICO-Hospital Germans Trias i Pujol, Institut de Recerca Contra la Leucemia Josep Carreras (IJC), Universitat Autonoma de Barcelona, Badalona, Spain 14 Laboratorio de Genetica Hematologica, Servicio de Hematologia, Hospital G.U. Gregorio Maranon, Instituto de Investigacion Sanitaria Gregorio Maranon, Madrid, Spain 15 Servicios de Genetica y Hematologia, Complejo Hospitalario de Navarra, Pamplona, Spain 16 Unidad de Genetica, Hospital Universitario La Fe, Valencia, Spain 17 Servei d’Hematologia, Hospital del Mar, Barcelona, Spain 18 Servicio de Hematologia, Hospital Universitario de Salamanca, IBSAL, IBMCC, Centro de Investigacion del Cancer, Universidad de Salamanca, CSIC, Salamanca, Spain 19 Servicio de Hematologia, Hospital Txagorritxu, Vitoria, Spain Correspondence to: Blanca Espinet, email: bespinet@parcdesalutmar.cat Keywords: CLL, TP53 aberrations, Chromosome 8 abnormalities, complex karyotype, prognosis Received: August 02, 2016      Accepted: October 27, 2016      Published: November 04, 2016 ABSTRACT Patients with chronic lymphocytic leukemia (CLL) harboring TP53 aberrations ( TP53 abs; Chromosome 17p deletion and/or TP53 mutation) exhibit an unfavorable clinical outcome. Chromosome 8 abnormalities, namely losses of 8p (8p−) and gains of 8q (8q+) have been suggested to aggravate the outcome of patients with TP53 abs. However, the reported series were small, thus hindering definitive conclusions. To gain insight into this issue, we assessed a series of 101 CLL patients harboring TP53 disruption. The frequency of 8p− and 8q+ was 14.7% and 17.8% respectively. Both were associated with a significantly ( P < 0.05) higher incidence of a complex karyotype (CK, ≥3 abnormalities) detected by Chromosome banding analysis (CBA) compared to cases with normal 8p (N-8p) and 8q (N-8q), respectively. In univariate analysis for 10-year overall survival (OS), 8p− ( P = 0.002), 8q+ ( P = 0.012) and CK ( P = 0.009) were associated with shorter OS. However, in multivariate analysis only CK (HR = 2.47, P = 0.027) maintained independent significance, being associated with a dismal outcome regardless of Chromosome 8 abnormalities. In conclusion, our results highlight the association of Chromosome 8 abnormalities with CK amongst CLL patients with TP53 abs, while also revealing that CK can further aggravate the prognosis of this aggressive subgroup.

Edward C Schwalbe - One of the best experts on this subject based on the ideXlab platform.

  • prognostic effect of whole chromosomal aberration signatures in standard risk non wnt non shh medulloblastoma a retrospective molecular analysis of the hit siop pnet 4 trial
    Lancet Oncology, 2018
    Co-Authors: Tobias Goschzik, Anja Zur Muehlen, Stefan Rutkowski, Edward C Schwalbe, Debbie Hicks, Amanda Smith, Dominique Figarellabranger, Francois Doz, Birgitta Lannering
    Abstract:

    Summary Background Most children with medulloblastoma fall within the standard-risk clinical disease group defined by absence of high-risk features (metastatic disease, large-cell/anaplastic histology, and MYC amplification), which includes 50–60% of patients and has a 5-year event-free survival of 75–85%. Within standard-risk medulloblastoma, patients in the WNT subgroup are established as having a favourable prognosis; however, outcome prediction for the remaining majority of patients is imprecise. We sought to identify novel prognostic biomarkers to enable improved risk-adapted therapies. Methods The HIT-SIOP PNET 4 trial recruited 338 patients aged 4–21 years with medulloblastoma between Jan 1, 2001, and Dec 31, 2006, in 120 treatment institutions in seven European countries to investigate hyperfractionated radiotherapy versus standard radiotherapy. In this retrospective analysis, we assessed the remaining tumour samples from patients in the HIT-SIOP PNET 4 trial (n=136). We assessed the clinical behaviour of the molecularly defined WNT and SHH subgroups, and identified novel independent prognostic markers and models for standard-risk patients with non-WNT/non-SHH disease. Because of the scarcity and low quality of available genomic material, we used a mass spectrometry-minimal methylation classifier assay (MS-MIMIC) to assess methylation subgroup and a molecular inversion probe array to detect genome-wide copy number aberrations. Prognostic biomarkers and models identified were validated in an independent, demographically matched cohort (n=70) of medulloblastoma patients with non-WNT/non-SHH standard-risk disease treated with conventional therapies (maximal surgical resection followed by adjuvant craniospinal irradiation [all patients] and chemotherapy [65 of 70 patients], at UK Children's Cancer and Leukaemia Group and European Society for Paediatric Oncology (SIOPE) associated treatment centres between 1990 and 2014. These samples were analysed by Illumina 450k DNA methylation microarray. HIT-SIOP PNET 4 is registered with ClinicalTrials.gov, number NCT01351870. Findings We analysed methylation subgroup, genome-wide copy number aberrations, and mutational features in 136 assessable tumour samples from the HIT-SIOP PNET 4 cohort, representing 40% of the 338 patients in the trial cohort. This cohort of 136 samples consisted of 28 (21%) classified as WNT, 17 (13%) as SHH, and 91 (67%) as non-WNT/non-SHH (we considered Group3 and Group4 medulloblastoma together in our analysis because of their similar molecular and clinical features). Favourable outcomes for WNT tumours were confirmed in patients younger than 16 years, and all relapse events in SHH (four [24%] of 17) occurred in patients with TP53 mutation ( TP53 mut ) or Chromosome 17p loss. A novel whole chromosomal aberration signature associated with increased ploidy and multiple non-random whole chromosomal aberrations was identified in 38 (42%) of the 91 samples from patients with non-WNT/non-SHH medulloblastoma in the HIT-SIOP PNET 4 cohort. Biomarkers associated with this whole chromosomal aberration signature (at least two of Chromosome 7 gain, Chromosome 8 loss, and Chromosome 11 loss) predicted favourable prognosis. Patients with non-WNT/non-SHH medulloblastoma could be reclassified by these markers as having favourable-risk or high-risk disease. In patients in the HIT-SIOP PNET4 cohort with non-WNT/non-SHH medulloblastoma, with a median follow-up of 6·7 years (IQR 5·8–8·2), 5-year event-free survival was 100% in the favourable-risk group and 68% (95% CI 57·5–82·7; p=0·00014) in the high-risk group. In the validation cohort, with a median follow-up of 5·6 years (IQR 3·1–8·1), 5-year event-free survival was 94·7% (95% CI 85·2–100) in the favourable-risk group and 58·6% (95% CI 45·1–76·1) in the high-risk group (hazard ratio 9·41, 95% CI 1·25–70·57; p=0·029). Our comprehensive molecular investigation identified subgroup-specific risk models which allowed 69 (51%) of 134 accessible patients from the standard-risk medulloblastoma HIT-SIOP PNET 4 cohort to be assigned to a favourable-risk group. Interpretation We define a whole chromosomal signature that allows the assignment of non-WNT/non-SHH medulloblastoma patients normally classified as standard-risk into favourable-risk and high-risk categories. In addition to patients younger than 16 years with WNT tumours, patients with non-WNT/non-SHH tumours with our defined whole chromosomal aberration signature and patients with SHH- TP53 wild-type tumours should be considered for therapy de-escalation in future biomarker-driven, risk-adapted clinical trials. The remaining subgroups of patients with high-risk medulloblastoma might benefit from more intensive therapies. Funding Cancer Research UK, Swedish Childhood Cancer Foundation, French Ministry of Health/French National Cancer Institute, and the German Children's Cancer Foundation.

  • biomarker driven stratification of disease risk in non metastatic medulloblastoma results from the multi center hit siop pnet4 clinical trial
    Oncotarget, 2015
    Co-Authors: Steven C Clifford, Tobias Goschzik, Edward C Schwalbe, Debbie Hicks, Dominique Figarellabranger, Birgitta Lannering, Kieran O Toole, Sarah Leigh Nicholson, Anja Zur Muhlen, Francois Doz
    Abstract:

    // Steven C. Clifford 1, * , Birgitta Lannering 2 , Ed C. Schwalbe 1, 3 , Debbie Hicks 1 , Kieran O' Toole 1 , Sarah Leigh Nicholson 1 , Tobias Goschzik 4 , Anja zur Muhlen 4 , Dominique Figarella-Branger 5 , Francois Doz 6 , Stefan Rutkowski 7 , Goran Gustafsson 8 , Torsten Pietsch 4, * , on behalf of the SIOP-Europe PNET Group 1 Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom 2 Department of Pediatrics, University of Gothenburg and The Queen Silvia Children's Hospital, Gothenburg, Sweden 3 Department of Applied Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom 4 Department of Neuropathology, University of Bonn, Bonn, Germany 5 Department of Pathology and Neuropathology, Assistance Publique Hopitaux de Marseille, Aix Marseille University, Marseille, France 6 Institut Curie and University Paris Descartes, Paris, France 7 University Medical Center Hamburg-Eppendorf, Hamburg, Germany 8 Karolinska Institute, Stockholm, Sweden * These authors have contributed equally to this work Correspondence to: Steven C. Clifford, e-mail: steve.clifford@ncl.ac.uk Keywords: medulloblastoma, clinical trial, biomarker, stratification Received: July 27, 2015      Accepted: August 24, 2015      Published: September 05, 2015 ABSTRACT Purpose: To improve stratification of risk-adapted treatment for non-metastatic (M0), standard-risk medulloblastoma patients by prospective evaluation of biomarkers of reported biological or prognostic significance, alongside clinico-pathological variables, within the multi-center HIT-SIOP-PNET4 trial. Methods: Formalin-fixed paraffin-embedded tumor tissues were collected from 338 M0 patients (>4.0 years at diagnosis) for pathology review and assessment of the WNT subgroup (MB WNT ) and genomic copy-number defects (Chromosome 17, MYC/MYCN , 9q22 ( PTCH1 ) and DNA ploidy). Clinical characteristics were reviewed centrally. Results: The favorable prognosis of MB WNT was confirmed, however better outcomes were observed for non-MB WNT tumors in this clinical risk-defined cohort compared to previous disease-wide clinical trials. Chromosome 17p/q defects were heterogeneous when assessed at the cellular copy-number level, and predicted poor prognosis when they occurred against a diploid (ch17(im)/diploid(cen)), but not polyploid, genetic background. These factors, together with post-surgical tumor residuum (R+) and radiotherapy delay, were supported as independent prognostic markers in multivariate testing. Notably, MYC and MYCN amplification were not associated with adverse outcome. In cross-validated survival models derived for the clinical standard-risk (M0/R0) disease group, (ch17(im)/diploid(cen); 14% of patients) predicted high disease-risk, while the outcomes of patients without (ch17(im)/diploid(cen)) did not differ significantly from MB WNT , allowing re-classification of 86% as favorable-risk. Conclusion: Biomarkers, established previously in disease-wide studies, behave differently in clinically-defined standard-risk disease. Distinct biomarkers are required to assess disease-risk in this group, and define improved risk-stratification models. Routine testing for specific patterns of Chromosome 17 imbalance at the cellular level, and MB WNT , provides a strong basis for incorporation into future trials.

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  • dna duplication associated with charcot marie tooth disease type 1a
    Cell, 1991
    Co-Authors: James R Lupski, David F Barker, Roberto Montes De Ocaluna, Susan A Slaugenhaupt, Liu Pentao, Vito Guzzetta, Barbara J Trask, Odila Saucedocardenas, James M Killian, Carlos A Garcia
    Abstract:

    Charcot-Marie-tooth disease type 1A (CMT1A) was localized by genetic mapping to a 3 cM interval on human Chromosome 17p. DNA markers within this interval revealed a duplication that is completely linked and associated with CMT1A. The duplication was demonstrated in affected individuals by the presence of three alleles at a highly polymorphic locus, by dosage differences at RFLP alleles, and by two-color fluorescence in situ hybridization. Pulsed-field gel electrophoresis of genomic DNA from patients of different ethnic origins showed a novel SacII fragment of 500 kb associated with CMT1A. A severely affected CMT1A offspring from a mating between two affected individuals was demonstrated to have this duplication present on each Chromosome 17. We have demonstrated that failure to recognize the molecular duplication can lead to misinterpretation of marker genotypes for affected individuals, identification of false recombinants, and incorrect localization of the disease locus.