111 results on '"Pierre W. Wijermans"'
Search Results
2. Monosomal karyotype and chromosome 17p loss or TP53 mutations in decitabine-treated patients with acute myeloid leukemia
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Lars Bullinger, Milena Pantic, Arnold Ganser, Pierre W. Wijermans, Björn Rüter, Anne Hagemeijer, Björn Hackanson, Dietmar Pfeifer, Hartmut Döhner, Gabriele Ihorst, Konstanze Döhner, Uwe Platzbecker, Michael Lübbert, Julius Wehrle, Andrea Kuendgen, Ulrich Germing, Justus Duyster, and Heiko Becker
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Oncology ,Male ,Cancer Research ,IMPACT ,DNA Mutational Analysis ,Gene mutation ,medicine.disease_cause ,Monosomy ,AML ,Germany ,TP53 ,DNA METHYLATION ,Aged, 80 and over ,Mutation ,Hematology ,SUBGROUP ANALYSIS ,Myeloid leukemia ,General Medicine ,Middle Aged ,COOPERATIVE GROUP ,Leukemia, Myeloid, Acute ,HYPOMETHYLATING AGENTS ,Cohort ,SURVIVAL ,Original Article ,Female ,Chromosome Deletion ,Life Sciences & Biomedicine ,Mutations ,medicine.drug ,medicine.medical_specialty ,Karyotype ,Decitabine ,Clonal Evolution ,Internal medicine ,SUPPORTIVE CARE ,medicine ,MYELODYSPLASTIC SYNDROMES ,Humans ,ddc:610 ,neoplasms ,Aged ,Science & Technology ,Acute myeloid leukemia ,OLDER PATIENTS ,business.industry ,Cytogenetics ,RANDOMIZED PHASE-III ,medicine.disease ,Survival Analysis ,Karyotyping ,Smith-Magenis Syndrome ,Tumor Suppressor Protein p53 ,business ,Chromosomes, Human, Pair 17 - Abstract
TP53 aberrations reportedly predict favorable responses to decitabine (DAC) in acute myeloid leukemia (AML). We evaluated clinical features and outcomes associated with chromosome 17p loss or TP53 gene mutations in older, unfit DAC-treated AML patients in a phase II trial. Of 178 patients, 25 had loss of 17p in metaphase cytogenetics; 24 of these had a complex (CK+) and 21 a monosomal karyotype (MK+). In analyses in all patients and restricted to CK+ and MK+ patients, 17p loss tended to associate with higher rates of complete remission (CR), partial remission (PR), or antileukemic effect (ALE). Despite favorable response rates, there was no significant OS difference between patients with or without loss of 17p in the entire cohort or in the CK+ and MK+ cohort. TP53 mutations were identified in eight of 45 patients with material available. Five of the eight TP53-mutated patients had 17p loss. TP53-mutated patients had similar rates of CR/PR/ALE but shorter OS than those with TP53 wild type (P = 0.036). Moreover, patients with a subclone based on mutation data had shorter OS than those without (P = 0.05); only one patient with TP53-mutated AML had a subclone. In conclusion, 17p loss conferred a favorable impact on response rates, even among CK+ and MK+ patients that however could not be maintained. The effect of TP53 mutations appeared to be different; however, patient numbers were low. Future research needs to further dissect the impact of the various TP53 aberrations in HMA-based combination therapies. The limited duration of favorable responses to HMA treatment in adverse-risk genetics AML should prompt physicians to advance allografting for eligible patients in a timely fashion.
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- 2020
3. Fetal hemoglobin induction during decitabine treatment of elderly patients with high-risk myelodysplastic syndrome or acute myeloid leukemia: a potential dynamic biomarker of outcome
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Julia Stomper, Pierre W. Wijermans, Gabriele Ihorst, Heiko Becker, Emmanuel Bissé, Christoph Plass, Philipp N. Sander, Dieter Weichenhan, Rainer Claus, Michael Lübbert, and Stefan Suciu
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Male ,Oncology ,medicine.medical_specialty ,Myeloid ,Decitabine ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Fetal hemoglobin ,Biomarkers, Tumor ,medicine ,Humans ,ddc:610 ,Fetal Hemoglobin ,Aged ,business.industry ,Hazard ratio ,Myeloid leukemia ,Hematology ,Middle Aged ,medicine.disease ,Neoplasm Proteins ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,Hypomethylating agent ,Myelodysplastic Syndromes ,Biomarker (medicine) ,Female ,K562 Cells ,business ,030215 immunology ,medicine.drug - Abstract
Hematologic responses to hypomethylating agents are often delayed in patients with myelodysplastic syndrome or acute myeloid leukemia. Fetal hemoglobin is a potential novel bio-marker of response: recently, we demonstrated that a high fetal hemoglobin level prior to decitabine treatment was associated with superior outcome. Here we investigated whether early fetal hemoglobin induction during decitabine treatment also had prognostic value, and studied the potential of decitabine to induce erythroid differentiation and fetal hemoglobin expression in vitro. Fetal hemoglobin levels were measured by high-performance liquid chromatography in patients with higher-risk myelodysplastic syndrome (n=16) and acute myeloid leukemia (n=37) before treatment and after each course of decitabine. Levels above 1.0% were considered induced. Patients achieving complete or partial remission as best response had attained a median fetal hemoglobin of 1.9% after two courses of treatment, whereas the median value in patients who did not reach complete or partial remission was 0.8% (P=0.015). Fetal hemoglobin induction after two courses of decitabine treatment was associated with early platelet doubling (P=0.006), and its subsequent decrease with hematologic relapse. In patients with myelodysplastic syndrome, induction of fetal hemoglobin after course 2 of treatment was associated with longer overall survival: median of 22.9 versus 7.3 months in patients with or without induction of fetal hemoglobin, respectively [hazard ratio=0.2 (95% confidence interval: 0.1–0.9); P=0.03]. In vitro decitabine treatment of two bi-potential myeloid leukemia cell lines (K562 and HEL) resulted in induction of an erythroid (not megakaryocytic) differentiation program, and of fetal hemoglobin mRNA and protein, associated with GATA1 gene demethylation and upregulation. In conclusion, fetal hemoglobin may provide a useful dynamic biomarker during hypomethylating agent therapy in patients with myelodysplastic syndrome or acute myeloid leukemia.
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- 2018
4. Genomic array as compared to karyotyping in myelodysplastic syndromes in a prospective clinical trial
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Eline M. P. Cremers, Saskia K. Klein, Petra Muus, Marian Stevens-Kroef, Georgine E. de Greef, Theresia M. Westers, Canan Alhan, Daniel Olde Weghuis, Pierre W. Wijermans, Sonia M Cunha, Najat ElIdrissi-Zaynoun, M Ron Schaafsma, Edo Vellenga, Gert J. Ossenkoppele, Arjan A. van de Loosdrecht, Bert A. van der Reijden, Dana A. Chitu, Heleen Visser-Wisselaar, and Joop H. Jansen
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Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.diagnostic_test ,Myelodysplastic syndromes ,Karyotype ,Biology ,Bioinformatics ,medicine.disease ,Uniparental disomy ,Loss of heterozygosity ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Genetics ,medicine ,SNP ,Virtual karyotype ,030215 immunology ,Fluorescence in situ hybridization ,SNP array - Abstract
Karyotyping is considered as the gold standard in the genetic subclassification of myelodysplastic syndrome (MDS). Oligo/SNP-based genomic array profiling is a high-resolution tool that also enables genome wide analysis. We compared karyotyping with oligo/SNP-based array profiling in 104 MDS patients from the HOVON-89 study. Oligo/SNP-array identified all cytogenetically defined genomic lesions, except for subclones in two cases and balanced translocations in three cases. Conversely, oligo/SNP-based genomic array profiling had a higher success rate, showing 55 abnormal cases, while an abnormal karyotype was found in only 35 patients. In nine patients whose karyotyping was unsuccessful because of insufficient metaphases or failure, oligo/SNP-based array analysis was successful. Based on cytogenetic visible abnormalities as identified by oligo/SNP-based genomic array prognostic scores based on IPSS/-R were assigned. These prognostic scores were identical to the IPSS/-R scores as obtained with karyotyping in 95%-96% of the patients. In addition to the detection of cytogenetically defined lesions, oligo/SNP-based genomic profiling identified focal copy number abnormalities or regions of copy neutral loss of heterozygosity that were out of the scope of karyotyping and fluorescence in situ hybridization. Of interest, in 26 patients we demonstrated such cytogenetic invisible abnormalities. These abnormalities often involved regions that are recurrently affected in hematological malignancies, and may therefore be of clinical relevance. Our findings indicate that oligo/SNP-based genomic array can be used to identify the vast majority of recurrent cytogenetic abnormalities in MDS. Furthermore, oligo/SNP-based array profiling yields additional genetic abnormalities that may be of clinical importance.
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- 2017
5. Graft-Versus-Leukemia effect of allogeneic stem-cell transplantation and minimal residual disease in patients with acute myeloid leukemia in first complete remission
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Carlos Graux, Mojca Jongen-Lavrencic, Thomas Pabst, Harry C. Schouten, Jurjen Versluis, Jakob Passweg, Jeroen Janssen, Vincent H.J. van der Velden, Marie-Christiane Vekemans, Mels Hoogendoorn, Wendelien Zeijlemaker, Burak Kalin, Okke de Weerdt, Marie-Cecile Legdeur, Pierre W. Wijermans, Marinus van Marwijk Kooy, Bart J. Biemond, Markus G. Manz, Gert J. Ossenkoppele, Gerrit Jan Schuurhuis, J. Kuball, Mario Bargetzi, Bob Löwenberg, Jan J. Cornelissen, Internal Medicine, Hematology, Immunology, UCL - (SLuc) Centre du cancer, UCL - SSS/IREC/SLUC - Pôle St.-Luc, and UCL - (SLuc) Service d'hématologie
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Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,03 medical and health sciences ,0302 clinical medicine ,Immunophenotyping ,SDG 3 - Good Health and Well-being ,hemic and lymphatic diseases ,Internal medicine ,medicine ,610 Medicine & health ,Chemotherapy ,business.industry ,Induction chemotherapy ,Myeloid leukemia ,Minimal residual disease ,Surgery ,body regions ,Transplantation ,Haematopoiesis ,030220 oncology & carcinogenesis ,Stem cell ,business ,030215 immunology - Abstract
Purpose The detection of minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) may improve future risk-adapted treatment strategies. We assessed whether MRD-positive and MRD-negative patients with AML benefit differently from the graft-versus-leukemia effect of allogeneic hematopoietic stem-cell transplantation (alloHSCT). Methods A total of 1,511 patients were treated in subsequent Dutch-Belgian Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research AML trials, of whom 547 obtained a first complete remission, received postremission treatment (PRT), and had available flow cytometric MRD before PRT. MRD positivity was defined as more than 0.1% cells with a leukemia-associated immunophenotype within the WBC compartment. PRT consisted of alloHSCT (n = 282), conventional PRT by a third cycle of chemotherapy (n = 160), or autologous hematopoietic stem-cell transplantation (n = 105). Results MRD was positive in 129 patients (24%) after induction chemotherapy before proceeding to PRT. Overall survival and relapse-free survival were significantly better in patients without MRD before PRT compared with MRD-positive patients (65% ± 2% v 50% ± 5% at 4 years; P = .002; and 58% ± 3% v 38% ± 4%; P < .001, respectively), which was mainly because of a lower cumulative incidence of relapse (32% ± 2% compared with 54% ± 4%; P < .001, respectively). Multivariable analysis with adjustment for covariables showed that the incidence of relapse was significantly reduced after alloHSCT compared with chemotherapy or autologous hematopoietic stem cell transplantation (hazard ratio [HR], 0.36; P < .001), which was similarly exerted in both MRD-negative and MRD-positive patients (HR, 0.38; P < .001; and HR, 0.35; P < .001, respectively). Conclusion The graft-versus-leukemia effect of alloHSCT is equally present in MRD-positive and MRD-negative patients, which advocates a personalized application of alloHSCT, taking into account the risk of relapse determined by AML risk group and MRD status, as well as the counterbalancing risk of nonrelapse mortality.
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- 2017
6. Clinical Results of Hypomethylating Agents in AML Treatment
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Gerwin Huls, Michael Lübbert, Pierre W. Wijermans, and Marjan Cruijsen
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Oncology ,medicine.medical_specialty ,azacitidine ,Azacitidine ,lcsh:Medicine ,Decitabine ,DNA Methyltransferase Inhibitor ,Review ,Pharmacology ,Gene mutation ,elderly ,AML ,Internal medicine ,medicine ,Epigenetics ,hypomethylating agents ,epigenetics ,business.industry ,lcsh:R ,Myeloid leukemia ,General Medicine ,Transplantation ,Toxicity ,business ,decitabine ,medicine.drug - Abstract
Epigenetic changes play an important role in the development of acute myeloid leukemia (AML). Unlike gene mutations, epigenetic changes are potentially reversible, which makes them attractive for therapeutic intervention. Agents that affect epigenetics are the DNA methyltransferase inhibitors, azacitidine and decitabine. Because of their relatively mild side effects, azacitidine and decitabine are particularly feasible for the treatment of older patients and patients with co-morbidities. Both drugs have remarkable activity against AML blasts with unfavorable cytogenetic characteristics. Recent phase 3 trials have shown the superiority of azacitidine and decitabine compared with conventional care for older AML patients (not eligible for intensive treatment). Results of treatment with modifications of the standard azacitidine (seven days 75 mg/m(2) SC; every four weeks) and decitabine (five days 20 mg/m(2) IV; every four weeks) schedules have been reported. Particularly, the results of the 10-day decitabine schedule are promising, revealing complete remission (CR) rates around 45% (CR + CRi (i.e., CR with incomplete blood count recovery) around 64%) almost comparable with intensive chemotherapy. Application of hypomethylating agents to control AML at the cost of minimal toxicity is a very promising strategy to "bridge" older patients with co-morbidities to the potential curative treatment of allogeneic hematopoietic cell transplantation. In this article, we discuss the role of DNA methyltransferase inhibitors in AML.
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- 2014
7. Randomized controlled trial on the effects of a supervised high intensity exercise program in patients with a hematologic malignancy treated with autologous stem cell transplantation: Results from the EXIST study
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Monique C. Minnema, Harry R. Koene, Frans Nollet, Pieternella J. Lugtenburg, Mai J. M. Chinapaw, Roberto D Liu, Pierre W. Wijermans, Marie José Kersten, Johannes Brug, Laurien M. Buffart, Saskia Persoon, Erik W.A. Marijt, APH - Societal Participation & Health, Graduate School, CCA - Cancer Treatment and Quality of Life, Other departments, AMS - Amsterdam Movement Sciences, Rehabilitation medicine, CCA -Cancer Center Amsterdam, Clinical Haematology, CCA - Cancer Treatment and quality of life, APH - Health Behaviors & Chronic Diseases, Public and occupational health, Epidemiology and Data Science, Division 6, Amsterdam Reproduction & Development (AR&D), APH - Methodology, Hematology, and Persuasive Communication (ASCoR, FMG)
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Male ,Lymphoma ,Physical fitness ,Cancer Treatment ,lcsh:Medicine ,High-Intensity Interval Training ,Pathology and Laboratory Medicine ,Biochemistry ,law.invention ,Grip strength ,0302 clinical medicine ,Autologous stem-cell transplantation ,Randomized controlled trial ,law ,Medicine and Health Sciences ,Medicine ,Single-Blind Method ,Public and Occupational Health ,030212 general & internal medicine ,lcsh:Science ,Physiotherapy ,Fatigue ,Multidisciplinary ,Agricultural and Biological Sciences(all) ,Middle Aged ,Sports Science ,Exercise Therapy ,Oncology ,030220 oncology & carcinogenesis ,Strength Training ,Female ,Multiple Myeloma ,High-intensity interval training ,Research Article ,Adult ,medicine.medical_specialty ,Randomization ,Drug-Related Side Effects and Adverse Reactions ,Strength training ,03 medical and health sciences ,Signs and Symptoms ,Diagnostic Medicine ,Intervention (counseling) ,Humans ,Sports and Exercise Medicine ,Exercise ,Aged ,business.industry ,Biochemistry, Genetics and Molecular Biology(all) ,lcsh:R ,Biology and Life Sciences ,Physical Activity ,Health Care ,Physical Fitness ,Physical therapy ,lcsh:Q ,business ,Genetics and Molecular Biology(all) - Abstract
Background: This single blind, multicenter randomized controlled trial aimed to evaluate the effectiveness of a supervised high intensity exercise program on physical fitness and fatigue in patients with multiple myeloma or lymphoma recently treated with autologous stem cell transplantation. Methods: 109 patients were randomly assigned to the 18-week exercise intervention or the usual care control group. The primary outcomes included physical fitness (VO2peak and Wpeak determined using a cardiopulmonary exercise test; grip strength and the 30s chair stand test) and fatigue (Multidimensional Fatigue Inventory) and were assessed prior to randomization and after completion of the intervention or at similar time points for the control group. Multivariable multilevel linear regression analyses were performed to assess intervention effects. Results: Patients in the intervention group attended 86% of the prescribed exercise sessions. Of the patients in the control group, 47% reported ≥10 physiotherapy sessions, which most likely included supervised exercise, suggesting a high rate of contamination. Median improvements in physical fitness ranged between 16 and 25% in the intervention group and between 12 and 19% in the control group. Fatigue decreased in both groups. There were no significant differences between the intervention and control group. Conclusion: We found no significant beneficial effects of the supervised high intensity exercise program on physical fitness and fatigue when compared to usual care. We hypothesized that the lack of significant intervention effects may relate to suboptimal timing of intervention delivery, contamination in the control group and/or suboptimal compliance to the prescribed exercise intervention. Trial registration: Netherlands Trial Register—NTR2341.
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- 2017
8. Implementation of erythroid lineage analysis by flow cytometry in diagnostic models for myelodysplastic syndromes
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Petra Muus, Pedro da Silva-Coelho, Theresia M. Westers, Edo Vellenga, Gert J. Ossenkoppele, Arjan A. van de Loosdrecht, Joop H. Jansen, Canan Alhan, Georgina E. de Greef, Vincent H.J. van der Velden, Jeroen G. te Marvelde, Eline M. P. Cremers, Saskia K. Klein, Marie Cecile J.C. Legdeur, Claudia Cali, Pierre W. Wijermans, Marian Stevens-Kroef, Dana A. Chitu, Heleen Visser-Wisselaar, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Stem Cell Aging Leukemia and Lymphoma (SALL), Hematology, Immunology, Hematology laboratory, CCA - Imaging and biomarkers, AGEM - Digestive immunity, and Internal medicine
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Adult ,Male ,medicine.medical_specialty ,Pathology ,Lineage (genetic) ,BONE-MARROW ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,Vascular damage Radboud Institute for Health Sciences [Radboudumc 16] ,WORLD-HEALTH-ORGANIZATION ,CLASSIFICATION ,VALIDATION ,Flow cytometry ,Immunophenotyping ,03 medical and health sciences ,0302 clinical medicine ,Erythroid Cells ,EUROPEAN LEUKEMIANET ,Internal medicine ,medicine ,Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14] ,Humans ,Cell Lineage ,DYSPLASIA ,INTERNATIONAL CONSORTIUM ,MYELOID NEOPLASMS ,Aged ,Aged, 80 and over ,UTILITY ,Hematology ,medicine.diagnostic_test ,business.industry ,Myelodysplastic syndromes ,Articles ,LEUKEMIANET WORKING GROUP ,Middle Aged ,medicine.disease ,Flow Cytometry ,medicine.anatomical_structure ,Dysplasia ,030220 oncology & carcinogenesis ,Case-Control Studies ,Myelodysplastic Syndromes ,Female ,Bone marrow ,business ,Biomarkers ,030215 immunology - Abstract
Contains fulltext : 169708.pdf (Publisher’s version ) (Open Access) Flow cytometric analysis is a recommended tool in the diagnosis of myelodysplastic syndromes. Current flow cytometric approaches evaluate the (im)mature myelo-/monocytic lineage with a median sensitivity and specificity of ~71% and ~93%, respectively. We hypothesized that the addition of erythroid lineage analysis could increase the sensitivity of flow cytometry. Hereto, we validated the analysis of erythroid lineage parameters recommended by the International/European LeukemiaNet Working Group for Flow Cytometry in Myelodysplastic Syndromes, and incorporated this evaluation in currently applied flow cytometric models. One hundred and sixty-seven bone marrow aspirates were analyzed; 106 patients with myelodysplastic syndromes, and 61 cytopenic controls. There was a strong correlation between presence of erythroid aberrancies assessed by flow cytometry and the diagnosis of myelodysplastic syndromes when validating the previously described erythroid evaluation. Furthermore, addition of erythroid aberrancies to two different flow cytometric models led to an increased sensitivity in detecting myelodysplastic syndromes: from 74% to 86% for the addition to the diagnostic score designed by Ogata and colleagues, and from 69% to 80% for the addition to the integrated flow cytometric score for myelodysplastic syndromes, designed by our group. In both models the specificity was unaffected. The high sensitivity and specificity of flow cytometry in the detection of myelodysplastic syndromes illustrates the important value of flow cytometry in a standardized diagnostic approach. The trial is registered at www.trialregister.nl as NTR1825; EudraCT n.: 2008-002195-10.
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- 2017
9. Bortezomib, melphalan, prednisone (VMP) versus melphalan, prednisone, thalidomide (MPT) in elderly newly diagnosed multiple myeloma patients: A retrospective case-matched study
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Pierre W. Wijermans, Pieter Sonneveld, Mario Boccadoro, Massimo Offidani, Alessandra Larocca, Jesús F. San Miguel, Valeria Magarotto, Meral Beksac, Gunnar Juliusson, Chiara Cerrato, Paola Omedè, Maria-Victoria Mateos, Pellegrino Musto, Antonio Palumbo, Anna Marina Liberati, Albert Oriol, Michele Cavo, Daniela Gottardi, Massimo Gentile, Sara Bringhen, Carla Mazzone, Fortunato Morabito, Davide Rossi, Ana Isabel Turel, Maide Cavalli, Peter Gimsing, Martijn R. Schaafsma, Roberto Passera, Sonja Zweegman, Anders Waage, Lucio Catalano, Juan José Lahuerta, Stefano Rosso, and Renato Zambello
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Melphalan ,medicine.medical_specialty ,Creatinine ,Bortezomib ,business.industry ,Case-control study ,Retrospective cohort study ,Hematology ,medicine.disease ,Gastroenterology ,Surgery ,Thalidomide ,chemistry.chemical_compound ,chemistry ,Prednisone ,Internal medicine ,medicine ,business ,Multiple myeloma ,medicine.drug - Abstract
Novel agents in combination with melphalan and prednisone (MP) significantly improved progression-free survival (PFS) and overall survival (OS) in multiple myeloma (MM). Randomized trials comparing MP plus bortezomib (VMP) versus MP plus thalidomide (MPT) are lacking. Nine hundred and fifty-six elderly (>65 years) newly diagnosed MM patients from six European randomized trials were retrospectively analyzed and matched for age, albumin, and beta2-microglobulin at diagnosis, 296 patients were selected from the VMP groups, and 294 from MPT. Complete response rate was 21% in the VMP patients and 13% in the MPT patients (P = 0.007). After a median follow-up of 34 months (range, 1-92), VMP significantly prolonged both PFS (median 32.5 vs. 22.9 months, HR 0.65; 95% CI 0.52-0.82; P < 0.001) and OS (median 79.7 vs. 45.1 months, HR 0.44; 95% CI 0.32-0.59; P < 0.001) in comparison with MPT. The benefit in terms of OS of the VMP group was quite similar among patients with different risk factors defined by sex, ISS, ECOG performance status, or serum creatinine but not among patients ≥ 75 years. Multivariate analysis confirmed that VMP was an independent predictor of longer PFS and OS. In a control-case matched analysis, PFS and OS were prolonged in patients who received VMP in comparison with those treated with MPT.
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- 2014
10. 10-day vs 5-day decitabine
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Gerwin Huls, Pierre W. Wijermans, Michal Kicinski, Michael Lübbert, Stefan Suciu, Stem Cell Aging Leukemia and Lymphoma (SALL), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
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Oncology ,medicine.medical_specialty ,Myeloid ,OLDER PATIENTS ,business.industry ,Azacitidine ,MEDLINE ,MULTICENTER ,Decitabine ,Hematology ,medicine.disease ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,Older patients ,Internal medicine ,medicine ,Humans ,business ,Equivalence (measure theory) ,Aged ,medicine.drug - Published
- 2019
11. The efficiency of therapeutic erythrocytapheresis compared to phlebotomy: A mathematical tool for predicting response in hereditary hemochromatosis, polycythemia vera, and secondary erythrocytosis
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Liane Van Egmond, Pierre W. Wijermans, Dorothea Evers, Jean-Louis H. Kerkhoffs, and Martin R. Schipperus
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medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Urology ,Blood volume ,Retrospective cohort study ,Hematology ,General Medicine ,Phlebotomy ,Hematocrit ,medicine.disease ,Surgery ,Polycythemia vera ,Hereditary hemochromatosis ,medicine ,business ,Hemochromatosis ,Blood drawing - Abstract
Recently, therapeutic erythrocytapheresis (TE) was suggested to be more efficient in depletion of red blood cells (RBC) compared to manual phlebotomy in the treatment of hereditary hemochromatosis (HH), polycythemia vera (PV), and secondary erythrocytosis (SE). The efficiency rate (ER) of TE, that is, the increase in RBC depletion achieved with one TE cycle compared to one phlebotomy procedure, can be calculated based on estimated blood volume (BV), preprocedural hematocrit (Hct(B)), and delta-hematocrit (ΔHct). In a retrospective evaluation of 843 TE procedures (in 45 HH, 33 PV, and 40 SE patients) the mean ER was 1.86 ± 0.62 with the highest rates achieved in HH patients. An ER of 1.5 was not reached in 37.9% of all procedures mainly concerning patients with a BV below 4,500 ml. In 12 newly diagnosed homozygous HH patients, the induction phase duration was medially 38.4 weeks (medially 10.5 procedures). During the maintenance treatment of HH, PV, and SE, the interval between TE procedures was medially 13.4 weeks. This mathematical model can help select the proper treatment modality for the individual patient. Especially for patients with a large BV and high achievable ΔHct, TE appears to be more efficient than manual phlebotomy in RBC depletion thereby potentially reducing the numbers of procedures and expanding the interprocedural time period for HH, PV, and SE.
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- 2013
12. A phase 2 multicentre study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with relapsed or refractory multiple myeloma
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Pierre W. Wijermans, Hong Xie, Peter M. Voorhees, Richard C. Frank, Robert Z. Orlowski, Brett Hall, Britte Kranenburg, Helgi van de Velde, Amrita Krishnan, Xiang Qin, Sonja Zweegman, Robert F. Manges, Sundar Jagannath, George Somlo, Tineke Casneuf, Suzanne Lentzsch, Sheeba K. Thomas, Pieter Sonneveld, Hematology, and CCA - Innovative therapy
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Oncology ,Adult ,Male ,medicine.medical_specialty ,Combination therapy ,Salvage therapy ,Antineoplastic Agents ,Kaplan-Meier Estimate ,Pharmacology ,Siltuximab ,Article ,Dexamethasone ,Drug Administration Schedule ,Bortezomib ,chemistry.chemical_compound ,Refractory ,Adrenal Cortex Hormones ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Multiple myeloma ,Aged ,Aged, 80 and over ,Salvage Therapy ,Infection Control ,business.industry ,Interleukin-6 ,Antibodies, Monoclonal ,Hematology ,Middle Aged ,medicine.disease ,Boronic Acids ,Hematologic Diseases ,Antibodies, Anti-Idiotypic ,Regimen ,C-Reactive Protein ,chemistry ,Drug Resistance, Neoplasm ,Pyrazines ,Disease Progression ,Female ,business ,Multiple Myeloma ,medicine.drug - Abstract
Interleukin-6 (IL6) plays a central role in multiple myeloma pathogenesis and confers resistance to corticosteroid-induced apoptosis. We therefore evaluated the efficacy and safety of siltuximab, an anti-IL6 monoclonal antibody, alone and in combination with dexamethasone, for patients with relapsed or refractory multiple myeloma who had ≥ 2 prior lines of therapy, one of which had to be bortezomib-based. Fourteen initial patients received siltuximab alone, 10 of whom had dexamethasone added for suboptimal response; 39 subsequent patients were treated with concurrent siltuximab and dexamethasone. Patients received a median of four prior lines of therapy, 83% were relapsed and refractory, and 70% refractory to their last dexamethasone-containing regimen. Suppression of serum C-reactive protein levels, a surrogate marker of IL6 inhibition, was demonstrated. There were no responses to siltuximab but combination therapy yielded a partial (17%) + minimal (6%) response rate of 23%, with responses seen in dexamethasone-refractory disease. The median time to progression, progression-free survival and overall survival for combination therapy was 4.4, 3.7 and 20.4 months respectively. Haematological toxicity was common but manageable. Infections occurred in 57% of combination-treated patients, including ≥ grade 3 infections in 18%. Further study of siltuximab in modern corticosteroid-containing myeloma regimens is warranted, with special attention to infection-related toxicity.
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- 2013
13. Elevated fetal haemoglobin is a predictor of better outcome in MDS/AML patients receiving 5-aza-2'-deoxycytidine (Decitabine)
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Pierre W. Wijermans, Gabriele Ihorst, Rainer Claus, Stefan Suciu, Ljudmila Bogatyreva, Philipp N. Sander, Emmanuel Bissé, Michael Lübbert, and Heiko Becker
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Oncology ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Antimetabolites, Antineoplastic ,Azacitidine ,Decitabine ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,Fetal hemoglobin ,medicine ,Humans ,Survival analysis ,Fetal Hemoglobin ,Aged ,Aged, 80 and over ,Proportional hazards model ,business.industry ,Myelodysplastic syndromes ,Hazard ratio ,Hematology ,DNA Methylation ,Middle Aged ,medicine.disease ,Prognosis ,Survival Analysis ,Leukemia, Myeloid, Acute ,030220 oncology & carcinogenesis ,Myelodysplastic Syndromes ,Biomarker (medicine) ,Female ,business ,Biomarkers ,030215 immunology ,medicine.drug - Abstract
Although azanucleoside DNA-hypomethylating agents (HMAs) are routinely used for the treatment of myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML), very few outcome predictors have been established. Expression of the β-like globin gene locus is tightly regulated by DNA methylation, is HMA-sensitive in vitro, and fetal haemoglobin (HbF) expression is under study as a potential biomarker for response of MDS patients to azacitidine. We determined HbF expression in 16 MDS and 36 AML patients receiving decitabine (DAC). Pre-treatment HbF was already elevated (>1·0% of total haemoglobin) in 7/16 and 12/36 patients, and HbF was induced by DAC in 81%/54% of MDS/AML patients, respectively. Elevated pre-treatment HbF was associated with longer median overall survival (OS): 26·6 vs. 8·6 months for MDS (hazard ratio [HR] 8·56, 95% confidence interval [CI] 1·74-42·49, P = 0·008, with similarly longer progression-free and AML-free survival), and 10·0 vs. 2·9 months OS for AML (HR 3·01, 95% CI 1·26-7·22, P = 0·014). In a multivariate analysis, the prognostic value of HbF was retained. Time-dependent Cox models revealed that the prognostic value of treatment-induced HbF induction was inferior to that of pre-treatment HbF. In conclusion, we provide first evidence for in vivo HbF induction by DAC in MDS/AML, and demonstrate prognostic value of elevated pre-treatment HbF, warranting prospective, randomized studies.
- Published
- 2016
14. Phase I/II trial of weekly bortezomib with lenalidomide and dexamethasone in first relapse or primary refractory myeloma
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Wendimagegn Ghidey Alemayehu, Marian Stevens-Kroef, S. Wittebol, Okke de Weerdt, Henk M. Lokhorst, Pierre W. Wijermans, Bea Tanis, Pieter Sonneveld, Marie José Kersten, Ellen Meijer, Mark-David Levin, Petra Cornelisse, Edo Vellenga, Gerard M. J. Bos, Annemiek Broijl, Amsterdam institute for Infection and Immunity, Cancer Center Amsterdam, Clinical Haematology, Interne Geneeskunde, MUMC+: MA Hematologie (9), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Stem Cell Aging Leukemia and Lymphoma (SALL), Hematology, and CCA - Clinical Therapy Development
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Salvage therapy ,Pharmacology ,first relapse ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14] ,Online Only Articles ,Hardware_REGISTER-TRANSFER-LEVELIMPLEMENTATION ,Multiple myeloma ,Dexamethasone ,Lenalidomide ,Bortezomib ,business.industry ,Hematology ,medicine.disease ,Thalidomide ,multiple myeloma ,030104 developmental biology ,escalated dose ,030220 oncology & carcinogenesis ,Proteasome inhibitor ,VRD ,business ,medicine.drug - Abstract
The use of the proteasome inhibitor bortezomib and immunomodulatory drugs such as thalidomide and lenalidomide have markedly improved outcome in patients with multiple myeloma (MM).[1][1] However, the majority of patients will eventually relapse, necessitating salvage therapy. HOVON 86 is a dose
- Published
- 2016
15. Parameters detected by geriatric and quality of life assessment in 195 older patients with myelodysplastic syndromes and acute myeloid leukemia are highly predictive for outcome
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Dominik Selleslag, Kurt Fritzsche, Eva März, Gabriele Ihorst, Uwe Platzbecker, Pierre W. Wijermans, Marcelo De Figuerido, Boris Labar, Ulrich Germing, Theo de Witte, Helmut R. Salih, Michael Lübbert, Peter Haas, Barbara Deschler, and Aristoteles Giagounidis
- Subjects
Male ,medicine.medical_specialty ,Myeloid ,Activities of daily living ,Editorials and Perspectives ,Quality of life ,Internal medicine ,Outcome Assessment, Health Care ,medicine ,Humans ,Geriatric Assessment ,Aged ,Aged, 80 and over ,business.industry ,Myelodysplastic syndromes ,Hazard ratio ,Translational research Immune Regulation [ONCOL 3] ,Myeloid leukemia ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Transplantation ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,Myelodysplastic Syndromes ,Quality of Life ,Physical therapy ,Female ,business - Abstract
Contains fulltext : 118926.pdf (Publisher’s version ) (Open Access) Myelodysplastic syndromes and acute myeloid leukemia exemplify the complexity of treatment allocation in older patients as options range from best supportive care, non-intensive treatment (e.g. hypomethylating agents) to intensive chemotherapy/hematopoietic cell transplantation. Novel metrics for non-disease variables are urgently needed to help define the best treatment for each older patient. We investigated the feasibility and prognostic value of geriatric/quality of life assessments aside from established disease-specific variables in 195 patients aged 60 years or over with myelodysplastic syndromes/acute myeloid leukemia. These patients were grouped according to treatment intensity and assessed. Assessment consisted of eight instruments evaluating activities of daily living, depression, mental functioning, mobility, comorbidities, Karnofsky Index and quality of life. Patients with a median age of 71 years (range 60-87 years) with myelodysplastic syndromes (n=63) or acute myeloid leukemia (n=132) were treated either with best supportive care (n=47), hypomethylating agents (n=73) or intensive chemotherapy/hematopoietic cell transplantation (n=75). After selection of variables, pathological activities of daily living and quality of life/fatigue remained highly predictive for overall survival in the entire patient group beyond disease-related risk factors adverse cytogenetics and blast count of 20% or over. In 107 patients treated non-intensively activities of daily living of less than 100 (hazard ratio, HR 2.94), Karnofsky Index below 80 (HR 2.34) and quality of life/'fatigue' of 50 or over (HR 1.77) were significant prognosticators. Summation of adverse features revealed a high risk of death (HR 9.36). In-depth evaluation of older patients prior to individual treatment allocation is feasible and provides additional information to standard assessment. Patients aged 60 years or over with newly diagnosed myelodysplastic syndromes/acute myeloid leukemia and impairments in activities of daily living, Karnofsky Index below 80%, quality of life/'fatigue' of 50 or over, are likely to have poor outcomes.
- Published
- 2012
16. Decitabine triphosphate levels in peripheral blood mononuclear cells from patients receiving prolonged low-dose decitabine administration: a pilot study
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Hilde Rosing, Robert S. Jansen, Jan H.M. Schellens, Ron J. Keizer, Pierre W. Wijermans, and Jos H. Beijnen
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Antimetabolites, Antineoplastic ,Cancer Research ,Pharmacology toxicology ,Decitabine ,Pilot Projects ,Pharmacology ,Toxicology ,Peripheral blood mononuclear cell ,Tandem Mass Spectrometry ,Humans ,Medicine ,Pharmacology (medical) ,business.industry ,Myelodysplastic syndromes ,Low dose ,medicine.disease ,Oncology ,Myelodysplastic Syndromes ,Azacitidine ,Leukocytes, Mononuclear ,business ,Nucleoside ,Intracellular ,Chromatography, Liquid ,medicine.drug - Abstract
Decitabine is a nucleoside analog used in the treatment for myelodysplastic syndrome. The compound requires intracellular conversion to its triphosphate to become active. Decitabine triphosphate has, however, never been quantified in peripheral blood mononuclear cells (PBMCs) from patients.This article describes a method for the quantitative determination of decitabine triphosphate in PBMCs using liquid chromatography coupled to tandem mass spectrometry. The method was applied to ex vivo incubated whole blood samples and samples from three patients receiving prolonged low-dose decitabine treatment.We successfully quantitated decitabine triphosphate in PBMCs. Considerable levels were detected in PBMCs from two patients that responded well to therapy, whereas only low levels were present in a non-responding patient. Moreover, the data show that, in contrast to plasma decitabine, intracellular decitabine triphosphate accumulates during a treatment cycle of nine infusions at a dose of 15 mg/m(2).The results suggest a relationship between decitabine triphosphate levels and response to therapy. Based on the observed accumulation of decitabine triphosphate during a treatment cycle, a less intensive dose scheme could be feasible.
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- 2012
17. Feasibility of nonselective testing for hemoglobinopathies in early pregnancy in The Netherlands
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Cisca Hudig, Judith O. Kaufmann, Pierre W. Wijermans, Liv M. Freeman, Gabrielle Ponjee, Gönül Demirel-Güngör, Jean-Louis H. Kerkhoffs, Gerard Steen, Cas Holleboom, Joris Hendiks, Piero C. Giordano, and Anke Selles
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Pediatrics ,medicine.medical_specialty ,education.field_of_study ,Anemia ,business.industry ,Population ,Obstetrics and Gynecology ,Gestational age ,Prenatal diagnosis ,Carrier testing ,medicine.disease ,Hemoglobinopathy ,medicine ,Family history ,Prospective cohort study ,business ,education ,Genetics (clinical) - Abstract
OBJECTIVE To examine the feasibility of standardized hemoglobinopathy (HBP) carrier testing for pregnant women in The Netherlands in addition to the standard anemia screening. METHODS We assessed the prevalence of HBP in women at the time of the first pregnancy visit using both a prospective cohort (N = 703) and a retrospective series of women selected at random (N = 588). For the purpose of analysis, the population was divided into a high risk and a low risk group for HBP based on maternal ethnicity. Screening for HBP utilized standard screening tests for anemia, with additional high performance liquid chromatography (Variant II); molecular analysis was performed by Gap-polymerase chain reaction (Gap-PCR) and if necessary, direct sequencing and multiplex ligation-dependent probe amplification (MLPA). Family history was reported or collected from the medical records. RESULTS β-Globin defects were found in 3.9% of the total population (50/1291). The frequency in the high risk population was 5.6% (37/656), compared with 1.2% (6/501) in the low risk group. In the prospective study we found 30 HBP carriers, leading to testing of 16 partners and identification of two couples at risk. One affected child was born. Mean gestational age at the screening was 11.3 weeks with a standard deviation (SD) of 5.8. CONCLUSION We found that the prevalence of HBP carriers is high enough in our population to warrant HBP testing for the entire multiethnic population in early pregnancy at the time of anemia screening. This is feasible as most women had their booking early in their first trimester.
- Published
- 2011
18. Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials
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Cyrille Hulin, Fabian Termorshuizen, Ingemar Turesson, Meral Beksac, Tommaso Caravita, Pieter Sonneveld, Lotfi Benboubker, Peter Fayers, Peter Gimsing, Pierre W. Wijermans, Philippe Moreau, Rauf Haznedar, Jean Yves Mary, Martijn R. Schaafsma, Pellegrino Musto, Sara Bringhen, Antonio Palumbo, Anders Waage, Thierry Facon, Radiology & Nuclear Medicine, and Hematology
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Melphalan ,Oncology ,Male ,medicine.medical_specialty ,Immunology ,Biochemistry ,law.invention ,Cohort Studies ,Randomized controlled trial ,law ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Clinical endpoint ,Humans ,Survival analysis ,Multiple myeloma ,Aged ,Randomized Controlled Trials as Topic ,Aged, 80 and over ,business.industry ,Hazard ratio ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Survival Analysis ,Neoadjuvant Therapy ,Surgery ,Thalidomide ,Regimen ,Prednisone ,Female ,business ,Multiple Myeloma ,medicine.drug - Abstract
The role of thalidomide for previously untreated elderly patients with multiple myeloma remains unclear. Six randomized controlled trials, launched in or after 2000, compared melphalan and prednisone alone (MP) and with thalidomide (MPT). The effect on overall survival (OS) varied across trials. We carried out a meta-analysis of the 1685 individual patients in these trials. The primary endpoint was OS, and progression-free survival (PFS) and 1-year response rates were secondary endpoints. There was a highly significant benefit to OS from adding thalidomide to MP (hazard ratio = 0.83; 95% confidence interval 0.73-0.94, P = .004), representing increased median OS time of 6.6 months, from 32.7 months (MP) to 39.3 months (MPT). The thalidomide regimen was also associated with superior PFS (hazard ratio = 0.68, 95% confidence interval 0.61-0.76, P < .0001) and better 1-year response rates (partial response or better was 59% on MPT and 37% on MP). Although the trials differed in terms of patient baseline characteristics and thalidomide regimens, there was no evidence that treatment affected OS differently according to levels of the prognostic factors. We conclude that thalidomide added to MP improves OS and PFS in previously untreated elderly patients with multiple myeloma, extending the median survival time by on average 20%.
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- 2011
19. Analysis of Efficacy and Prognostic Factors of Lenalidomide Treatment as Part of a Dutch Compassionate Use Program
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Monique C. Minnema, Marinus H. J. van Oers, Edo Vellenga, Sonja Zweegman, Shulamiet Wittebol, Reinier Raymakers, Gerwin Huls, Pieter Sonneveld, Pierre W. Wijermans, Marie José Kersten, Martijn R. Schaafsma, Corien Eeltink, Jan Koedam, Evelien Kneppers, Henk M. Lokhorst, Hematology, CCA - Innovative therapy, Amsterdam institute for Infection and Immunity, Cancer Center Amsterdam, Clinical Haematology, Faculteit Medische Wetenschappen/UMCG, Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Stem Cell Aging Leukemia and Lymphoma (SALL)
- Subjects
Adult ,Compassionate Use Trials ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,PLUS DEXAMETHASONE ,Myeloma ,THERAPY ,Dexamethasone ,Bortezomib ,Recurrence ,REFRACTORY MULTIPLE-MYELOMA ,Internal medicine ,medicine ,Humans ,Relapse ,COMBINATION ,Lenalidomide ,Multiple myeloma ,Aged ,Aged, 80 and over ,Clinical Trials as Topic ,Performance status ,Refractory ,business.industry ,Thalidomide resistance ,Research ,Stem cell transplantation ,Hematology ,Middle Aged ,medicine.disease ,Boronic Acids ,Thalidomide ,Surgery ,Transplantation ,Pyrazines ,Disease Progression ,T-CELLS ,Female ,Multiple Myeloma ,business ,medicine.drug - Abstract
Background and Methods: To obtain efficacy and safety data on lenalidomide treatment outside of clinical trials, we analyzed the clinical data of 114 patients with refractory or relapsed multiple myeloma treated with lenalidomide on a compassionate use basis. The recommended treatment consisted of lenalidomide 25 mg given on days 1-21 of a 28-day cycle, in combination with dexamethasone. A median of 3 previous lines of therapy were given, including thalidomide in 91%. Most patients were treated until progression or intolerable toxicity. Results: The median number of cycles was 7 (range, 1-21 + cycles) with a maximum response after a median of 3 cycles (range, 1-10 cycles). The overall response rate was 69%, including complete response in 6%, very good partial response in 19%, and partial response in 44%. The response rate was not influenced by previous thalidomide and/or bortezomib treatment. The median time to progression (TTP) was 9 months and the median overall survival (OS) was 22 months. A significantly longer TTP was observed in patients who previously underwent allogeneic stem cell transplantation (12.5 months vs. 8 months; P = .036). Overall survival was significantly affected by performance status (P = 3) and the incidence of venous thrombotic events was low (5%) using the recommended prophylaxis. Conclusion: This analysis confirms that, outside clinical prospective trials, treatment with lenalidomide is highly effective and feasible in heavily pretreated patients with multiple myeloma.
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- 2010
20. Value of allogeneic versus autologous stem cell transplantation and chemotherapy in patients with myelodysplastic syndromes and secondary acute myeloid leukemia. Final results of a prospective randomized European Intergroup Trial
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Harald Biersack, Jean-Pierre Marie, Stefan Suciu, Joop H. Jansen, Petra Muus, Alois Gratwohl, Pierre W. Wijermans, Dominik Selleslag, Roel Willemze, Anne Hagemeijer, Eva Hellström-Lindberg, Tibor Kovacsovics, Sergio Amadori, Amin Belhabri, Gert J. Ossenkoppele, Harry C. Schouten, Augustin Ferrant, Michel Delforge, Guido Kobbe, Theo de Witte, Interne Geneeskunde, and RS: GROW - School for Oncology and Reproduction
- Subjects
Oncology ,medicine.medical_specialty ,autologous stem cell transplantation ,medicine.medical_treatment ,Medizin ,Autologous stem-cell transplantation ,allogeneic stem cell transplantation ,Immune Regulation [NCMLS 2] ,Translational research [ONCOL 3] ,Internal medicine ,Medicine ,Survival analysis ,Chemotherapy ,business.industry ,intensive chemotherapy ,Myelodysplastic syndromes ,Hazard ratio ,Hematology ,cytogenetic characteristics ,medicine.disease ,myelodysplastic syndromes ,Surgery ,Transplantation ,Leukemia ,Cytarabine ,Original Article ,secondary acute myeloid leukemia ,business ,medicine.drug - Abstract
Contains fulltext : 87519.pdf (Publisher’s version ) (Open Access) BACKGROUND: Allogeneic stem cell transplantation is usually considered the only curative treatment option for patients with advanced or transformed myelodysplastic syndromes in complete remission, but post-remission chemotherapy and autologous stem cell transplantation are potential alternatives, especially in patients over 45 years old. DESIGN AND METHODS: We evaluated, after intensive anti-leukemic remission-induction chemotherapy, the impact of the availability of an HLA-identical sibling donor on an intention-to treat basis. Additionally, all patients without a sibling donor in complete remission after the first consolidation course were randomized to either autologous peripheral blood stem cell transplantation or a second consolidation course consisting of high-dose cytarabine. RESULTS: The 4-year survival of the 341 evaluable patients was 28%. After achieving complete remission, the 4-year survival rates of patients under 55 years old with or without a donor were 54% and 41%, respectively, with an adjusted hazard ratio of 0.81 (95% confidence interval [95% CI], 0.49-1.35) for survival and of 0.67 (95% CI, 0.42-1.06) for disease-free survival. In patients with intermediate/high risk cytogenetic abnormalities the hazard ratio in multivariate analysis was 0.58 (99% CI, 0.22-1.50) (P=0.14) for survival and 0.46 (99% CI, 0.22-1.50) for disease-free survival (P=0.03). In contrast, in patients with low risk cytogenetic characteristics the hazard ratio for survival was 1.17 (99% CI, 0.40-3.42) and that for disease-free survival was 1.02 (99% CI, 0.40-2.56). The 4-year survival of the 65 patients randomized to autologous peripheral blood stem cell transplantation or a second consolidation course of high-dose cytarabine was 37% and 27%, respectively. The hazard ratio in multivariate analysis was 1.22 (95% CI, 0.65-2.27) for survival and 1.02 (95% CI, 0.56-1.85) for disease-free survival. CONCLUSIONS: Patients with a donor and candidates for allogeneic stem cell transplantation in first complete remission may have a better disease-free survival than those without a donor in case of myelodysplastic syndromes with intermediate/high-risk cytogenetics. Autologous peripheral blood stem cell transplantation does not provide longer survival than intensive chemotherapy. 01 oktober 2010
- Published
- 2010
21. A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma
- Author
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Okke de Weerdt, Gerard M. J. Bos, Harm Sinnige, Sonja Zweegman, Pieter Sonneveld, Kon-Siong G. Jie, Shulamiet Wittebol, Pierre W. Wijermans, Marinus H. J. van Oers, Sandra Croockewit, Edo Vellenga, Monique C. Minnema, Henk M. Lokhorst, Bronno van der Holt, Henriette Berenschot, Michel Delforge, P. Joosten, Marinus van Marwijk-Kooy, Peter A. von dem Borne, Rianne Ammerlaan, R. Schaafsma, Amsterdam institute for Infection and Immunity, Cancer Center Amsterdam, Clinical Haematology, Hematology, Erasmus MC other, Faculteit Medische Wetenschappen/UMCG, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Stem Cell Aging Leukemia and Lymphoma (SALL), CCA - Innovative therapy, Interne Geneeskunde, and RS: GROW - School for Oncology and Reproduction
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Male ,Melphalan ,medicine.medical_treatment ,PLUS DEXAMETHASONE ,Phases of clinical research ,Biochemistry ,THERAPY ,Dexamethasone ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,ELDERLY-PATIENTS ,Multiple myeloma ,LENALIDOMIDE ,ABNORMALITIES ,Remission Induction ,Hematology ,Middle Aged ,CHEMOTHERAPY ,Prognosis ,Thalidomide ,Survival Rate ,Treatment Outcome ,SURVIVAL ,Female ,TRIAL ,Multiple Myeloma ,medicine.drug ,Adult ,medicine.medical_specialty ,Adolescent ,Immunology ,Urology ,Young Adult ,Translational research [ONCOL 3] ,Humans ,NEWLY-DIAGNOSED MYELOMA ,Survival rate ,Aged ,Neoplasm Staging ,Lenalidomide ,Chemotherapy ,business.industry ,STEM-CELL TRANSPLANTATION ,Cell Biology ,medicine.disease ,Surgery ,Doxorubicin ,business - Abstract
Contains fulltext : 87501.pdf (Publisher’s version ) (Closed access) The phase 3 trial HOVON-50 was designed to evaluate the effect of thalidomide during induction treatment and as maintenance in patients with multiple myeloma who were transplant candidates. A total of 556 patients was randomly assigned to arm A: 3 cycles of vincristine, adriamycin, and dexamethasone, or to arm B: thalidomide 200 mg orally, days 1 to 28 plus adriamycin and dexamethasone. After induction therapy and stem cell mobilization, patients were to receive high-dose melphalan, 200 mg/m(2), followed by maintenance with alpha-interferon (arm A) or thalidomide 50 mg daily (arm B). Thalidomide significantly improved overall response rate as well as quality of the response before and after high dose melphalan. Best overall response rate on protocol was 88% and 79% (P = .005), at least very good partial remission 66% and 54% (P = .005), and complete remission 31% and 23% (P = .04), respectively, in favor of the thalidomide arm. Thalidomide also significantly improved event-free survival from median 22 months to 34 months (P < .001), and prolonged progression free from median 25 months to 34 months (P < .001). Median survival was longer in the thalidomide arm, 73 versus 60 months; however, this difference was not significant (P = .77). Patients randomized to thalidomide had strongly reduced survival after relapse. This trial was registered on www.controlled-trials.com as ISRCTN06413384.
- Published
- 2010
22. Dose-finding study of imatinib in combination with intravenous cytarabine: feasibility in newly diagnosed patients with chronic myeloid leukemia
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H. Berna Beverloo, Jan J. Cornelissen, Anton Schattenberg, Hanneke C. Kluin-Nelemans, Jeroen Janssen, Pierre W. Wijermans, Gregor Verhoef, Peter J. M. Valk, Augustin Ferrant, Marie José Kersten, Bob Löwenberg, Pieter Sonneveld, Bronno van der Holt, Willem M. Smit, Gert J. Ossenkoppele, S. Wittebol, Marinus van Marwijk Kooy, Petra H. M. Westveer, Roelof Willemze, Wendy Deenik, Leo F. Verdonck, Hematology, IOO, Dermatology, Pathology, CCA - Innovative therapy, Faculteit Medische Wetenschappen/UMCG, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Stem Cell Aging Leukemia and Lymphoma (SALL), Clinical Genetics, AII - Amsterdam institute for Infection and Immunity, CCA -Cancer Center Amsterdam, and Clinical Haematology
- Subjects
Male ,CHROMOSOME ,medicine.medical_treatment ,FEATURES ,Pharmacology ,Biochemistry ,Gastroenterology ,Piperazines ,RECOMMENDATIONS ,BRAIN-ABSCESS ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Molecular diagnosis, prognosis and monitoring [UMCN 1.2] ,Hematologic Tests ,CHRONIC MYELOGENOUS LEUKEMIA ,Cytarabine ,Myeloid leukemia ,Hematology ,Middle Aged ,Benzamides ,Cytogenetic Analysis ,Injections, Intravenous ,Imatinib Mesylate ,Female ,TYROSINE KINASE INHIBITOR ,Physical Organic Chemistry ,medicine.drug ,Adult ,INTERFERON ,medicine.medical_specialty ,Combination therapy ,medicine.drug_class ,Immunology ,MESYLATE ,Antineoplastic Agents ,Antimetabolite ,Communicable Diseases ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,NEUTROPENIC PATIENTS ,Humans ,Mortality ,Aged ,Chemotherapy ,Dose-Response Relationship, Drug ,business.industry ,CHRONIC-PHASE ,Imatinib ,Cell Biology ,medicine.disease ,Imatinib mesylate ,Pyrimidines ,Feasibility Studies ,business ,Chronic myelogenous leukemia - Abstract
Contains fulltext : 70504schattenberg.pdf (Publisher’s version ) (Closed access) The HOVON cooperative study group performed a feasibility study of escalated imatinib and intravenous cytarabine in 165 patients with early chronic-phase chronic myeloid leukemia (CML). Patients received 2 cycles of intravenous cytarabine (200 mg/m(2) or 1000 mg/m(2) days 1-7) in conjunction with imatinib (200 mg, 400 mg, 600 mg, or 800 mg), according to predefined, successive dose levels. All dose levels proved feasible. Seven dose-limiting toxicities (DLTs) were observed in 302 cycles of chemotherapy, which were caused by streptococcal bacteremia in 5 cases. Intermediate-dose cytarabine (1000 mg/m(2)) prolonged time to neutrophil recovery and platelet recovery compared with a standard dose (200 mg/m(2)). High-dose imatinib (600 mg or 800 mg) extended the time to platelet recovery compared with a standard dose (400 mg). More infectious complications common toxicity criteria (CTC) grade 3 or 4 were observed after intermediate-dose cytarabine compared with a standard-dose of cytarabine. Early response data after combination therapy included a complete cytogenetic response in 48% and a major molecular response in 30% of patients, which increased to 46% major molecular responses at 1 year, including 13% complete molecular responses. We conclude that combination therapy of escalating dosages of imatinib and cytarabine is feasible. This study was registered at www.kankerbestrijding.nl as no. CKTO-2001-03. 8 p.
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- 2008
23. Rituximab improves the treatment results of DHAP-VIM-DHAP and ASCT in relapsed/progressive aggressive CD20(+) NHL: a prospective randomized HOVON trial
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Wim L.J. van Putten, Gustaaf W. van Imhoff, Marinus H. J. van Oers, Josée M. Zijlstra, Mars B. van 't Veer, Leo F. Verdonck, Pierre W. Wijermans, Peter C. Huijgens, Edo Vellenga, Pieternella J. Lugtenburg, Willem E. Fibbe, Hematology, and CCA - Innovative therapy
- Subjects
Male ,Oncology ,CHOP ,Biochemistry ,Dexamethasone ,Antibodies, Monoclonal, Murine-Derived ,International Prognostic Index ,Recurrence ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Prospective Studies ,ELDERLY-PATIENTS ,Etoposide ,Remission Induction ,Cytarabine ,Antibodies, Monoclonal ,BONE-MARROW TRANSPLANTATION ,Hematology ,Middle Aged ,Chemotherapy regimen ,Survival Rate ,PROGNOSTIC INDEX PREDICTS ,Female ,Rituximab ,medicine.drug ,Adult ,medicine.medical_specialty ,Lymphoma, B-Cell ,Adolescent ,Immunology ,Transplantation, Autologous ,Disease-Free Survival ,Internal medicine ,DHAP ,RELAPSED LYMPHOMA ,Humans ,NON-HODGKINS-LYMPHOMA ,CHEMOTHERAPY PLUS RITUXIMAB ,Ifosfamide ,Progression-free survival ,Aged ,Performance status ,business.industry ,B-CELL LYMPHOMA ,INTERMEDIATE-GRADE ,Cell Biology ,Surgery ,Transplantation ,Methotrexate ,Cisplatin ,business ,HIGH-DOSE THERAPY ,Follow-Up Studies ,Stem Cell Transplantation - Abstract
We evaluated the role of rituximab during remission induction chemotherapy in relapsed aggressive CD20+ non-Hodgkin lymphoma. Of 239 patients, 225 were evaluable for analysis. Randomized to DHAP (cisplatin-cytarabine-dexamethasone)-VIM (etoposide-ifosfamide-methotrexate)-DHAP (cisplatin-cytarabine-dexamethasone) chemotherapy with rituximab (R; R-DHAP arm) were 119 patients (113 evaluable) and to chemotherapy without rituximab (DHAP arm) 120 patients (112 evaluable). Patients in complete remission (CR) and partial remission (PR) after 2 chemotherapy courses were eligible for autologous stem-cell transplantation. After the second chemotherapy cycle, 75% of the patients in the R-DHAP arm had responsive disease (CR or PR) versus 54% in the DHAP arm (P = .01). With a median follow-up of 24 months, there was a significant difference in failure-free survival (FFS24; 50% vs 24% vs, P < .001), and progression free survival (PFS24; 52% vs 31% P < .002) in favor of the R-DHAP arm. Cox-regression analysis demonstrated a significant effect of rituximab treatment on FFS24 (HR 0.41, 95% confidence interval [CI] 0.29-0.57 versus 0.51, 95% CI 0.37-0.70) and overall-survival (OS24: HR 0.60 [0.41-0.89] vs 0.76 [0.52-1.10]) when adjusted for time since upfront treatment, age, World Health Organization performance status, and secondary age-adjusted international prognostic index. These results demonstrate improved FFS and PFS for relapsed aggressive B-cell NHL if rituximab is added to the re-induction chemotherapy regimen.
- Published
- 2008
24. Hb Lepore-Leiden: A New δ/β Rearrangement Associated with a β-Thalassemia Minor Phenotype
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Pierre W. Wijermans, Cornelis L. Harteveld, Piero C. Giordano, Sandra G.J. Arkesteijn, Jean-Louis H. Kerkhoffs, and Peter van Delft
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Genetics ,Hemolytic anemia ,Biochemistry (medical) ,Clinical Biochemistry ,Hepatosplenomegaly ,Prenatal diagnosis ,Hematology ,Biology ,Compound heterozygosity ,medicine.disease ,Phenotype ,Hemoglobinopathy ,medicine ,medicine.symptom ,Beta (finance) ,Gene ,Genetics (clinical) - Abstract
The Lepore hemoglobins (Hbs) are a group of structural defects resulting from different recombination events between the delta- and beta-globin genes. They may come with different beta-thalassemia (beta-thal) minor-like phenotypes in the carrier and with variably severe phenotypes in the rare homozygote, and in the common compound heterozygote with beta-thal. The most seriously affected patients are those of Yugoslavian origin presenting with severe transfusion-dependent hemolytic anemia, dyserythropoiesis, hepatosplenomegaly and skeletal malformations. Because of genetic risk, couples where both partners are carriers of these combinations may require prognosis and prenatal diagnosis. In these cases, recognition of the defect must be done with particular care. We report a case of Hb Lepore induced by a yet unknown crossover event found in a 24-year-old Turkish male and compare the novel mutation with those previously reported.
- Published
- 2008
25. Extended follow up of high-dose melphalan and autologous stem cell transplantation after vincristine, doxorubicin, dexamethasone induction in amyloid light chain amyloidosis of the prospective phase II HOVON-41 study by the Dutch-Belgian Co-operative Trial Group for Hematology Oncology
- Author
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Marinus H. J. van Oers, Bronno van der Holt, Michel Delforge, Pierre W. Wijermans, Sonja Zweegman, Bouke P. C. Hazenberg, Pieter Sonneveld, Peter A. von dem Borne, Alexandra J. Croockewit, Okke de Weerdt, Henk M. Lokhorst, Fokje M. Spoelstra, Gerard M. J. Bos, Reinier Raymakers, Edo Vellenga, RS: GROW - Oncology, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Hematology, Erasmus MC other, Amsterdam institute for Infection and Immunity, Cancer Center Amsterdam, Clinical Haematology, Translational Immunology Groningen (TRIGR), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Stem Cell Aging Leukemia and Lymphoma (SALL), and CCA - Innovative therapy
- Subjects
Melphalan ,Adult ,Male ,medicine.medical_specialty ,BORTEZOMIB ,Kaplan-Meier Estimate ,Gastroenterology ,Transplantation, Autologous ,Dexamethasone ,Autologous stem-cell transplantation ,MULTIPLE-MYELOMA ,Internal medicine ,CYCLOPHOSPHAMIDE ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,AL amyloidosis ,Humans ,Survival rate ,Multiple myeloma ,Aged ,LENALIDOMIDE ,NATRIURETIC PEPTIDE ,business.industry ,Amyloidosis ,Remission Induction ,AL AMYLOIDOSIS ,Hematopoietic Stem Cell Transplantation ,Hematology ,Articles ,CHEMOTHERAPY ,Middle Aged ,medicine.disease ,Combined Modality Therapy ,Surgery ,Transplantation ,MAINTENANCE ,Treatment Outcome ,Doxorubicin ,Vincristine ,SURVIVAL ,Female ,business ,PRIMARY SYSTEMIC AMYLOIDOSIS ,Primary systemic amyloidosis ,medicine.drug ,Follow-Up Studies - Abstract
In a prospective multicenter phase II study, we evaluated the effect of three courses of vincristine, doxorubicin and dexamethasone followed by high-dose melphalan and autologous stem cell transplantation on an intention-to-treat basis. Sixty-nine newly diagnosed patients with amyloid light chain amyloidosis were included between November 2000 and January 2006: 37 men and 32 women with a median age of 56 years, including 46% of patients with cardiac and 22% of patients with involvement of 3 or 4 organs. Initial results presented in 2008 showed a 4-year overall survival rate of 62% among all the patients, while the 4-year survival rate after transplantation was 78%. Here we report the long-term follow-up data after a median follow up of 115 months of the patients still alive. Median survival of all patients was 96 months from registration and for the transplanted patients ten years from the date of transplantation. Twelve (12%) patients died during induction therapy with vincristine, doxorubicin and dexamethasone, including 8 patients (12%) due to treatment-related mortality. Two patients died within one month following high-dose melphalan. We conclude that vincristine, doxorubicin and dexamethasone should not be applied as induction therapy for intensification in amyloid light chain amyloidosis. However, a 2-step approach consisting of a non-intensive less toxic induction therapy followed by high-dose melphalan and autologous stem cell transplantation may result in extended survival in newly diagnosed patients with amyloid light chain amyloidosis (clinicaltrials.gov identifier: 01207094).
- Published
- 2015
26. Decitabine versus best supportive care in older patients with refractory anemia with excess blasts in transformation (RAEBt) - results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group (GMDSSG)
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Theo de Witte, Carlo Aul, Hans-Eckart Schaefer, Aristoteles Giagounidis, Stefan Suciu, Ulrich Germing, Pierre W. Wijermans, Michael Lübbert, Björn Rüter, Anne Hagemeijer, Helmut R. Salih, Uwe Platzbecker, Heiko Becker, Boris Labar, Karl-Heinz Pflüger, Arnold Ganser, Petra Muus, Valeria Fiaccadori, Frédéric Baron, and Dominik Selleslag
- Subjects
Male ,medicine.medical_specialty ,Antimetabolites, Antineoplastic ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,medicine.medical_treatment ,Vascular damage Radboud Institute for Health Sciences [Radboudumc 16] ,Azacitidine ,Decitabine ,Hematopoietic stem cell transplantation ,Disease-Free Survival ,Internal medicine ,medicine ,Humans ,Survival rate ,Aged ,Aged, 80 and over ,Anemia, Refractory, with Excess of Blasts ,business.industry ,Myelodysplastic syndromes ,Hazard ratio ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,Surgery ,Survival Rate ,Leukemia ,Cohort ,Female ,business ,Blast Crisis ,medicine.drug - Abstract
Item does not contain fulltext In the European Organisation for Research and Treatment of Cancer (EORTC)/GMDSSG phase III trial 06011, we compared decitabine (15 mg/m(2) every 8 h for 3 days) with best supportive care (BSC) in patients >/=60 years with myelodysplastic syndromes (MDS) by French-American-British (FAB) criteria. Here, we reinvestigate trial 06011 for the activity and efficacy specifically in patients with refractory anemia with excess blasts in transformation (RAEBt). Response rates in the decitabine arm (N = 40) were as follows: complete or partial remission, 15 %; hematologic improvement, 15 %; resistant disease, 30 %. RAEBt patients in the decitabine arm had longer progression-free survival (PFS; hazard ratio (HR) 0.30, 95 % confidence interval (CI) 0.18-0.51; median, 6.2 vs 2.8 months) and overall survival (OS; HR 0.68, 95 % CI 0.42-1.11; median, 8.0 vs 6.0 months) than in the BSC arm (N = 35). Censoring at allogeneic hematopoietic stem cell transplantation, the OS difference between the treatment groups increased, particularly among patients aged 60-74 years (HR 0.48, 95 % CI 0.26-0.89). After regrouping the study cohort according to World Health Organization (WHO) criteria, patients with acute myeloid leukemia (AML) (i.e., >/=20 % blasts) in the decitabine arm (N = 27) also had longer PFS than in the BSC arm (N = 23) (HR 0.46, 95 % CI 0.26-0.83; median, 6.2 vs 2.8 months). In conclusion, 3-day decitabine displays clinical activity and efficacy in MDS and/or AML with 5-30 % blood or 20-30 % marrow blasts.
- Published
- 2015
27. Treatment of myelodysplastic syndrome with a DNA methyltransferase inhibitor: Lack of evidence for induction of chromosomal instability
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Peter Haas, Michael Lübbert, Gregor Verhoef, and Pierre W. Wijermans
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Male ,Antimetabolites, Antineoplastic ,Cancer Research ,Monosomy ,Azacitidine ,Decitabine ,Biology ,chemistry.chemical_compound ,Chromosomal Instability ,Chromosome instability ,medicine ,Humans ,Metaphase ,Aged ,Myelodysplastic syndromes ,Hematology ,Middle Aged ,medicine.disease ,Demethylating agent ,Oncology ,chemistry ,Myelodysplastic Syndromes ,Cytogenetic Analysis ,Immunology ,DNA methylation ,Cancer research ,Female ,Deoxycytidine ,Chromosome Deletion ,Follow-Up Studies ,medicine.drug - Abstract
In several large phase II trials, low-dose treatment with the azanucleoside 5-aza-2'-deoxycytidine (decitabine, DAC) resulted in complete hematologic and cytogenetic responses in 23 and 31% of MDS patients, respectively. The question of induction of chromosomal instability by this demethylating agent was addressed by serial karyotypic analyses. 53/122 DAC-treated patients had all normal metaphases at time of treatment start. In 46/53 patients, sequential cytogenetic analyses were performed. 9/46 patients (20%) acquired clonal chromosomal abnormalities during follow-up (4/9 transient). 8/9 abnormalities were gains or losses of entire chromosomes. The rate and pattern of cytogenetic evolution are thus not higher than in historical MDS cohorts not receiving specific treatment.
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- 2006
28. Superiority of prolonged low-dose azanucleoside administration?
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Pierre W. Wijermans, Michael Lübbert, and Björn Rüter
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Male ,Antimetabolites, Antineoplastic ,Cancer Research ,medicine.medical_specialty ,Decitabine ,chemistry.chemical_compound ,Recurrence ,Risk Factors ,Internal medicine ,medicine ,Humans ,Aged ,Aged, 80 and over ,business.industry ,Myelodysplastic syndromes ,Low dose ,Induction chemotherapy ,Cancer ,Middle Aged ,medicine.disease ,Response to treatment ,Surgery ,Survival Rate ,Oncology ,chemistry ,International Prognostic Scoring System ,Myelodysplastic Syndromes ,Retreatment ,Azacitidine ,Disease Progression ,Female ,Deoxycytidine ,business ,medicine.drug - Abstract
BACKGROUND The optimal treatment duration with decitabine (DAC) in patients with myelodysplastic syndromes (MDS) remains a matter of debate. Although at least 2 consolidating courses after best response usually are performed, the response to treatment after disease recurrence has not been systematically studied to date. METHODS In the current study, the authors report on 22 of 108 patients with MDS (20%) treated with low-dose DAC in 3 Phase II trials who received DAC as retreatment at the time of disease recurrence. RESULTS According to the International Prognostic Scoring System (IPSS) at the time of initial treatment, 5 of 22 patients (23%) had a score of intermediate-1 (Int-1), 4 patients (18%) had a score of Int-2, and 13 patients (59%) were scored as high-risk. Patients initially received a median of 6 courses of DAC (range, 2 courses-6 courses), which resulted in a complete remission (complete response [CR]) in 12 of the 22 patients (55%). Retreatment with DAC at the time of disease recurrence was initiated at a median of 11 months (range, 3 mos-27 mos) after the last course of initial treatment. With regard to DAC retreatment, patients received a median of 3 courses (range, 1 courses-6 courses), with 10 of 22 patients (45%) responding (1 with a CR and 2 with partial remissions [partial response (PR)]; all 3 patients achieved a CR at the time of initial treatment) and 7 patients demonstrating a hematologic improvement (HI) (at the time of initial treatment there were 2 CRs, 4 PRs, and 1 HI). Twelve of the 22 patients (55%) did not demonstrate any objective responses to retreatment, including 4 patients with primary resistance to the first course of retreatment. The median survival of all patients from the initiation of the first DAC course was 27.5 months (range, 15 mos-50+ mos). The median survival of 43 patients who also had achieved a response to the initial treatment with DAC but who received best supportive care (n = 33 patients) or induction chemotherapy (n = 10 patients) was 18 months (range, 5 mos-72 mos). Second responders to DAC retreatment were found less frequently in the IPSS high-risk group compared with nonresponders (40% vs. 83%). Age, French–American–British classification subtype, serum lactate dehydrogenase level at retreatment, and previous response to DAC were not found to strongly differ between the groups; however, the subgroups were too small to perform a statistical analysis. CONCLUSIONS Retreatment with DAC was found to result in objective responses in 45% of previously DAC-responsive patients. However, the quality and duration of the second disease remissions were found to be inferior. Therefore, DAC-responsive patients might derive more clinical benefit from continuation of the initial treatment. Cancer 2006. © 2006 American Cancer Society.
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- 2006
29. In vivo effects of decitabine in myelodysplasia and acute myeloid leukemia: review of cytogenetic and molecular studies
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Christian Robbel, Michael Lübbert, Björn Hackanson, and Pierre W. Wijermans
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Antimetabolites, Antineoplastic ,medicine.medical_specialty ,Azacitidine ,Decitabine ,Biology ,Epigenesis, Genetic ,Mice ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Animals ,Humans ,Cyclin-Dependent Kinase Inhibitor p15 ,Chromosome Aberrations ,Chromosome 7 (human) ,Clinical Trials as Topic ,Hematology ,Cytogenetics ,Myeloid leukemia ,General Medicine ,DNA Methylation ,medicine.disease ,Leukemia ,Leukemia, Myeloid ,Myelodysplastic Syndromes ,Acute Disease ,Immunology ,Cancer research ,Hemoglobin F ,medicine.drug - Abstract
Low-dose demethylating agents such as 5-aza-2'-deoxycytidine (decitabine, DAC) and 5-azacytidine (azacitidine, Vidaza) have been explored for the treatment of myelodysplasia, acute myeloid leukemia, and hemoglobinopathies since the early 1980s, aiming to revert a methylator phenotype. Originally, the treatment rationale in hemoglobinopathies was to achieve demethylation of the hypermethylated and hence silent gamma-globin gene locus, thus reactivating synthesis of hemoglobin F (HbF). In myelodysplastic syndrome (MDS), cytogenetic analyses are mandatory for risk stratification and for monitoring response to drug treatment. The current knowledge regarding cytogenetic subgroups as predictors of response to low-dose decitabine in MDS as well as cytogenetic responses caused by demethylating agents is summarized in this review. Decitabine treatment is associated with a response rate that is higher in patients with high-risk cytogenetics (i.e., complex karyotype and/or abnormalities of chromosome 7) than in patients with intermediate-risk cytogenetics (two abnormalities or single abnormalities excluding 5q-, 20q-, and -Y). Following decitabine treatment of patients with abnormal karyotype, approximately one-third achieve a major cytogenetic response that can be confirmed by FISH analyses, while in two-thirds of patients, the abnormal karyotype persists but hematologic improvement may be observed during continued treatment. The most frequently studied gene in myelodysplasia is the cell cycle regulator p15(INK4b). Hypermethylation of p15(INK4b) in MDS is reversed during treatment with decitabine, resulting in reactivation of this gene. In hemoglobinopathies, treatment with demethylating agents leads to reactivation of fetal HbF (the gamma-globin gene locus also possibly being another target for reactivation in MDS), and thus, HbF may potentially act as surrogate marker for activity of decitabine. Other, thus far unidentified hypermethylated genes may also be targets for demethylating agents.
- Published
- 2005
30. Impact of three courses of intensified CHOP prior to high-dose sequential therapy followed by autologous stem-cell transplantation as first-line treatment in poor-risk, aggressive non-Hodgkin's lymphoma
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Monique M.C. Steijaert, Harry C. Schouten, Leo F. Verdonck, Pierre W. Wijermans, Hanneke C. Kluin-Nelemans, Bronno van der Holt, Pieter Sonneveld, M.A. MacKenzie, Gustaaf W. van Imhoff, Gerrit J. Ossenkoppele, Philip M. Kluin, Mars B. van't Veer, Hematology, Cardiology, Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Stem Cell Aging Leukemia and Lymphoma (SALL)
- Subjects
Oncology ,Melphalan ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Adolescent ,CHOP ,Transplantation, Autologous ,Autologous stem-cell transplantation ,Risk Factors ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,LNH87-2 ,Humans ,BENEFIT ,Cyclophosphamide ,Etoposide ,Aged ,Carmustine ,business.industry ,Lymphoma, Non-Hodgkin ,Remission Induction ,Immunotherapy, gene therapy and transplantation [UMCN 1.4] ,INTERMEDIATE-GRADE ,1ST COMPLETE REMISSION ,Middle Aged ,CHEMOTHERAPY ,medicine.disease ,Prognosis ,Combined Modality Therapy ,BONE-MARROW-TRANSPLANTATION ,RANDOMIZED-TRIAL ,Non-Hodgkin's lymphoma ,Transplantation ,Survival Rate ,Treatment Outcome ,Doxorubicin ,Vincristine ,Cytarabine ,Prednisone ,Female ,Mitoxantrone ,business ,medicine.drug ,Stem Cell Transplantation - Abstract
Purpose Timing, appropriate amount, and composition of treatment before high-dose therapy and autologous stem-cell transplantation (ASCT) in patients with poor-risk, aggressive non-Hodgkin's lymphoma (NHL) are still unknown. We conducted two consecutive multicenter phase II trials with up-front, high-dose, sequential chemotherapy and ASCT in poor-risk, aggressive NHL. Both trials had identical inclusion criteria and only differed in amount and duration of induction treatment before ASCT. Patients and Methods Between 1994 and 2001, 147 newly diagnosed, poor-risk, aggressive NHL patients, age ≤ 65 years with stage III to IV and lactate dehydrogenase (LDH) more than 1.5× upper limit of normal (ULN), entered the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) -27 and HOVON-40 trials. Treatment in HOVON-27 consisted of two up-front, high-dose induction courses followed by carmustine, etoposide, cytarabine, and melphalan plus ASCT in responding patients. In HOVON-40, the same treatment was preceded by three intensified courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Results Patient characteristics in both trials were comparable: 80% had diffuse large B-cell lymphoma, 77% had stage IV disease, and median LDH levels were 3.1× ULN. Complete remission (CR) in both trials was 45% to 51%. Before ASCT, CR was 14% in HOVON-27 versus 28% in HOVON-40 (P = .03). Treatment failure was similar (27%). Four-year survival estimates in HOVON-27 compared with HOVON-40 were overall survival, 21% v 50% (P = .007); event-free survival, 15% v 49% (P = .0001); and disease-free survival, 34% v 74% (P = .008). This different outcome favoring HOVON-40 remained highly significant when correcting for competing risk factors in multivariate analysis. Conclusion In patients with poor-risk, aggressive NHL, addition of intensified CHOP before up-front, high-dose, sequential therapy and ASCT significantly improved the duration of response and survival.
- Published
- 2005
31. Nonclonal neutrophil responses after successful treatment of myelodysplasia with low-dose 5-aza-2’-deoxycytidine (decitabine)
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Yalin Guo, Pierre W. Wijermans, Monika Engelhardt, Michael Daskalakis, Regina Kunzmann, and Michael Lübbert
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,Neutropenia ,Neutrophils ,Population ,Decitabine ,Granulocyte ,Biology ,Leukocyte Count ,chemistry.chemical_compound ,medicine ,Humans ,education ,In Situ Hybridization, Fluorescence ,Aged ,Cell Proliferation ,education.field_of_study ,Cytogenetics ,Hematology ,medicine.disease ,Clone Cells ,Haematopoiesis ,medicine.anatomical_structure ,Oncology ,chemistry ,Myelodysplastic Syndromes ,Immunology ,Azacitidine ,Female ,Leukopoiesis ,Deoxycytidine ,Bone marrow ,Granulocytes ,medicine.drug - Abstract
The demethylating agents 5-aza-2'-deoxycytidine (decitabine, DAC) and 5-azacytidine at low doses induce hematologic and cytogenetic remissions in a subset of patients with MDS. It is unclear whether the correction of neutropenia involves differentiation of abnormal granulocyte precursors, or emergence of normal granulopoiesis. A previous study in three MDS patients, analyzing a differentiating activity of GM-CSF, had shown heterogenous granulocyte responses. The objective of our study was to determine the ratio of clonal and nonclonal peripheral blood granulocytes in MDS patients treated with DAC using FISH analysis. In two patients with initial severe neutropenia, an informative cytogenetic marker, complete normalization of peripheral blood neutrophils and a bone marrow cytogenetic response following DAC, >90% of the cells contributing to neutrophil normalization lacked this clonal marker. In one of them, an early and transient increase in clonal neutrophils was compatible also with a modest differentiating effect upon the dysplastic granulocyte precursors, whereas in a third patient, resistant to re-treatment with DAC, no expansion of either granulocyte population occurred. In the responders, leukocyte nadirs following DAC appeared less pronounced after conversion to normal cytogenetics. In conclusion, restoration of nonclonal hematopoiesis may be the predominant effect of DAC both in early and late stages of treatment, at least in patients achieving a hematologic and cytogenetic response.
- Published
- 2004
32. Addition of cyclosporin A to the combination of mitoxantrone and etoposide to overcome resistance to chemotherapy in refractory or relapsing acute myeloid leukaemia
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Mark H.H Kramer, Monique Steijaert, Bob Löwenberg, Pierre W. Wijermans, Rien van Marwijk Kooy, Peter C. Huijgens, Gregor Verhoef, Simon Daenen, Harry C. Schouten, Leo F. Verdonck, Bronno van der Holt, Pieter Sonneveld, Augustin Ferrant, and Eva van den Berg
- Subjects
Oncology ,Cancer Research ,Chemotherapy ,medicine.medical_specialty ,Mitoxantrone ,business.industry ,medicine.medical_treatment ,Hematology ,Transplantation ,Refractory ,Cyclosporin a ,Internal medicine ,Toxicity ,Medicine ,business ,Survival analysis ,Etoposide ,medicine.drug - Abstract
Cyclosporin A (CsA) inhibits the P-gp pump that can be responsible for failure of cytostatic treatment in acute myeloid leukaemia (AML). Eighty patients with relapsing/refractory AML were randomly assigned to mitoxantrone (M) and etoposide (VP) (MVP) in unmitigated antileukaemic doses with or without CsA, to investigate if toxicity was manageable and if antileukaemic therapy could be improved. CsA did not delay haematological recovery, but fewer CsA patients received post-induction therapy because of haematological and non-haematological toxicity. CR rate was 43% for MVP and 53% for CsA; DFS was 9 and 8 months, and OS 8 and 9 months, respectively. Seventeen of 38 CR patients proceeded to stem cell transplantation (SCT). After a median follow-up of 66 months, six patients were still alive. Addition of CsA did not improve treatment outcome, possibly due to inadequate post-induction therapy as a result of increased toxicity.
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- 2004
33. The importance of antibodies against low-incidence RBC antigens in complete and abbreviated cross-matching
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Henk Schonewille, Pierre W Wijermans, and Annette M. Van Zijl
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medicine.medical_specialty ,Hematology ,biology ,business.industry ,Incidence (epidemiology) ,Immunology ,Autoantibody ,Transfusion History ,Serology ,Antigen ,Internal medicine ,medicine ,biology.protein ,Immunology and Allergy ,Antibody ,Prospective cohort study ,business - Abstract
BACKGROUND: It is common practice to perform an antiglobulin cross-match only when unexpected RBC alloantibodies are present, to detect antibodies against additional RBC antigens. In this study, the incidence of unexpected antibodies to low-incidence antigens (Ab-LIA) over a period of 23 years was investigated. STUDY DESIGN AND METHODS: Records of RBC antibodies and the accompanying transfusion history from 1978 through 2000 was retrospectively examined. Complete cross-matches were performed for all RBC transfusions before 1991. As of 1991, the type-and-screen policy was applied. To study the incidence of anti-Wra, a prospective study was conducted on sera from 462 patients sent to the transfusion laboratory and 486 blood donors. RESULTS: The records of 1795 patients containing 2257 RBC antibodies were examined. In 89 patients, a total of 94 Ab-LIAs was found. Anti-Wra was the most frequently encountered Ab-LIA. Thirty-nine patients had Ab-LIA in combination with other antibodies, 20 of which were autoantibodies. Eighty percent of these Ab-LIA were found at the first positive antibody screening test. Fifty-one solitary Ab-LIA were found in 50 patients, 37 during antibody screening tests, and 14 after positive complete cross-matches conducted before 1991. After an RBC antibody was detected, 664 patients received a total of 7792 RBC transfusions. Since the introduction of the type-and-screen policy, only one anti-Wra has been discovered during complete cross-matching. No transfusion reactions due to Ab-LIA were reported during the study period. In the prospective study, 12.3 percent of patients and 4.3 percent of blood donors had anti-Wra. CONCLUSIONS: Although Ab-LIAs are found coincidentally in the sera of only 2 to 3 percent of patients with other RBC antibodies, they are formed often. Because we found no difference in serologic incompatibility, due to Ab-LIAs, between patients with and without other blood group antibodies, we conclude that blood can be transfused safely to patients without performing a complete cross-match.
- Published
- 2003
34. Bortezomib before and after autologous stem cell transplantation overcomes the negative prognostic impact of renal impairment in newly diagnosed multiple myeloma: a subgroup analysis from the HOVON-65/GMMG-HD4 trial
- Author
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Michael Pfreundschuh, Marinus van Marwijk-Kooy, Mathias Hänel, Hartmut Goldschmidt, Kai Neben, M Ron Schaafsma, Walter Lindemann, Ingo G.H. Schmidt-Wolf, Gerard M. J. Bos, Uta Bertsch, Christof Scheid, Norma Peter, Pieter Sonneveld, Sonja Zweegman, Henk M. Lokhorst, Igor Wolfgang Blau, Katja Weisel, Laila el Jarari, Hans Martin, Helgi van de Velde, Edo Vellenga, Kon-Siong G. Jie, Pierre W. Wijermans, Marie José Kersten, Shulamiet Wittebol, Ulrich Duehrsen, Hans Salwender, Sandra Croockewit, Bronno van der Holt, Hematology, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Stem Cell Aging Leukemia and Lymphoma (SALL), RS: GROW - Oncology, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, CCA - Innovative therapy, AII - Amsterdam institute for Infection and Immunity, CCA -Cancer Center Amsterdam, and Clinical Haematology
- Subjects
medicine.medical_treatment ,Medizin ,Hematopoietic stem cell transplantation ,Bortezomib ,chemistry.chemical_compound ,Autologous stem-cell transplantation ,FAILURE ,Renal Insufficiency ,Multiple myeloma ,LENALIDOMIDE ,INDUCTION ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Hematology ,Articles ,Middle Aged ,Boronic Acids ,DEXAMETHASONE ,Treatment Outcome ,Creatinine ,Pyrazines ,Multiple Myeloma ,Autologous ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,medicine.drug ,Adult ,PREDNISONE ,medicine.medical_specialty ,DOXORUBICIN ,Urology ,Editorials and Perspectives ,Antineoplastic Agents ,Transplantation, Autologous ,medicine ,MANAGEMENT ,Humans ,THALIDOMIDE ,Survival rate ,Lenalidomide ,Aged ,Transplantation ,business.industry ,medicine.disease ,Surgery ,Thalidomide ,MAINTENANCE ,chemistry ,MELPHALAN ,business - Abstract
Contains fulltext : 137125.pdf (Publisher’s version ) (Open Access) Renal impairment is frequent in patients with multiple myeloma and is correlated with an inferior prognosis. This analysis evaluates the prognostic role of renal impairment in patients with myeloma treated with bortezomib before and after autologous stem cell transplantation within a prospective randomized phase III trial. Eight hundred and twenty-seven newly diagnosed myeloma patients in the HOVON-65/GMMG-HD4 trial were randomized to receive three cycles of vincristine, adriamycin, dexamethasone (VAD) or bortezomib, adriamycin, dexamethasone (PAD) followed by autologous stem cell transplantation and maintenance with thalidomide 50 mg daily (VAD-arm) or bortezomib 1.3 mg/m(2) every 2 weeks (PAD-arm). Baseline serum creatinine was less than 2 mg/dL (Durie-Salmon-stage A) in 746 patients and 2 mg/dL or higher (stage B) in 81. In myeloma patients with a baseline creatinine >/= 2 mg/dL the renal response rate was 63% in the VAD-arm and 81% in the PAD-arm (P=0.31). The overall myeloma response rate was 64% in the VAD-arm versus 89% in the PAD-arm with 13% complete responses in the VAD-arm versus 36% in the PAD-arm (P=0.01). Overall survival at 3 years for patients with a baseline creatinine >/= 2 mg/dL was 34% in the VAD-arm versus 74% in the PAD-arm (P/= 2 mg/dL or
- Published
- 2014
35. Lenalidomide with or without Erythropoietin and Granulocyte-Colony Stimulating Factor Shows Efficacy in Patients with Low and Intermediate-1 Risk Myelodysplastic Syndrome with or without Del 5q, Refractory or Unlikely to Respond to Erythropoietin. Results of a HOVON89 Phase II Randomized Multicenter Study. (EudraCT 2008-002195-10)
- Author
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Canan Alhan, Marie-Cecile Legdeur, Petra Muus, Edo Vellenga, Dana A. Chitu, Bea Tanis, Saskia K. Klein, Inge de Greef, Heleen Visser-Wisselaar, Gert J. Ossenkoppele, Arjan A. van de Loosdrecht, Jurgen Wegman, Annelies Verbrugge, Wendy Deenik, Eline M. P. Cremers, Theresia M. Westers, Mojca Jongen-Lavrencic, Rien van Marwijk-Kooy, Tanja van Maanen, Joop H. Jansen, and Pierre W. Wijermans
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Blood transfusion ,medicine.medical_treatment ,Immunology ,Phases of clinical research ,Biochemistry ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,Internal medicine ,Medicine ,Adverse effect ,Lenalidomide ,business.industry ,Cell Biology ,Hematology ,Surgery ,Granulocyte colony-stimulating factor ,030104 developmental biology ,Erythropoietin ,030220 oncology & carcinogenesis ,Erythropoietin Measurement ,business ,medicine.drug - Abstract
Purpose: This randomized phase II study (HOVON89) in patients with low/int-1 risk MDS refractory or unlikely to respond to erythropoietin and granulocyte-colony stimulating factor (EPO/G-CSF) assessed efficacy and safety of lenalidomide without (Arm A) or with EPO+/-G-CSF (Arm B) in case of no erythroid response after 4 cycles. Patients and methods: In total 200 patients were randomly 1:1 assigned to either Arm A or Arm B. All patients were treated with lenalidomide (10 mg/day/day 1-21) for a minimum of 6 months in arm A and 12 months in arm B or until loss of response or disease progression. Patients in arm B without hematological improvement-erythroid (HI-E) after 4 cycles received EPO (30,000 IU/wk). In those patients who did not show HI-E after 6 months, EPO was increased to 60,000 IE/wk. G-CSF (3x 300-480 µg/wk) was added if no HI-E was reached at 8 month. The current pre-final evaluation was based on the first180 patients and included 85% non-del5q MDS and15% patients with isolated del5q. The median age was 71years (range 38-89). No differences were observed between both arms regarding sex (55% male), WHO PS, WHO diagnostic subgroup and IPSS, baseline Hb, WBC, platelets, endogenous erythropoietin level, pretreatment with EPO+/-G-CSF (67% of the patients were pretreated) and pre-study transfusions. Patients had received a median of 13 (range 0-72) units of RBC and 4 (range 0-13) within 8 weeks for prior study entry. Results: Adverse events were consistent with the known safety profile of lenalidomide/EPO/G-CSF. HI-E according to IWG criteria was achieved in 38% and 41% of the patients for arm A and B, respectively (p = 0.46). HI-E was significantly lower in non-del5q versus del5q patients (33% vs 78%, respectively). Time-to-HI-E was 3.1 months (median; range 1.6-12.3) for both arms with a median duration of 10 months (range 1 - 76). The median PFS was 14.4 vs 15.4 months in arms A and B (p=0.43). OS was 51.1 and 37.7 months for arm A and B (p=0.09). At 2 years 17% of patients had progressed to AML (no differences between arms). The median FU of patients still alive is 31 months. PFS and OS was significantly longer in those who achieved HI-E, (median 13 vs 19 months, p=0.02 for PFS and median 31 vs 63 months for OS, p Conclusion: Lenalidomide yields sustained HI-E in 33% of patients with non-del5q low/int-1 risk MDS refractory or unlikely to respond on EPO/G-CSF. The addition of EPO/G-CSF did not improve HI-E. Achievement of HI-E significantly improves PFS and OS. Disclosures Ossenkoppele: J&J: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria; Karyopharm: Consultancy, Research Funding; Novartis: Research Funding.
- Published
- 2016
36. Elevated Pre-Treatment Fetal Hemoglobin Predicts Better Outcome in MDS/AML Patients Receiving 5-Aza-2'-Deoxycytidine (DAC)
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Heiko Becker, Michael Lübbert, Pierre W. Wijermans, Stefan Suciu, Emmanuel Bissé, Rainer Claus, Philipp N. Sander, Gabriele Ihorst, and Ljudmila Bogatyreva
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Proportional hazards model ,Immunology ,Azacitidine ,Induction chemotherapy ,Cell Biology ,Hematology ,Biochemistry ,Gemcitabine ,Surgery ,chemistry.chemical_compound ,chemistry ,hemic and lymphatic diseases ,Internal medicine ,Fetal hemoglobin ,Cytarabine ,Medicine ,Deoxycytidine ,business ,Prospective cohort study ,medicine.drug - Abstract
Introduction: Aberrant DNA methylation occurs frequently in hematologic malignancies and is associated with altered gene expression. Consequently, DNA hypomethylating agents (HMAs), e.g. 5-aza-2'-deoxycytidine (DAC), have been tested for in vivo demethylation and have become accepted as first-line treatment of older MDS and AML patients (pts). While HMAs are already routinely used for the treatment of MDS and AML, only very few outcome predictors have been established thus far. Expression of the β-like globin gene locus is tightly regulated by methylation, is HMA-sensitive in vitro, and fetal hemoglobin (HbF) expression is under study as a potential biomarker for response of MDS pts to 5-azacytidine. Here, we present the first study of serial HbF measurements in MDS and AML pts receiving DAC in order to investigate a potential clinical application of HbF as a predictor of outcome to this treatment. Methods: 16 MDS and 36 AML pts enrolled on two clinical trials, the 06011 EORTC-GMDSSG phase III trial of higher-risk MDS, and the 00331 phase II trial of older, non-fit AML pts (Lübbert M et al., Haematologica 2012), were treated with DAC. MDS pts received nine 4-hour infusions of 15 mg/m2 given over 72 hours, repeated every 6 weeks for a minimum of four courses. AML pts were treated with nine 3-hour infusions of 15 mg/m2 given over 72 hours, repeated every 6 weeks for four courses followed by maintenance treatment with DAC at 20 mg/m2 when responding (defined by CR, PR or an antileukemic effect). HbF levels were measured in peripheral blood by HPLC before treatment and sequentially, i. e. after the end of each treatment course (every 6 weeks). HbF levels >1% of total hemoglobin were considered elevated. Results: Baseline HbF was elevated (>1.0%) in 7/16 MDS and 12/36 AML pts. Clinical baseline characteristics were uniformly distributed between pts with normal and elevated HbF levels. HbF induction was observed in 81% of MDS pts after a median of 2 (range 2-6) courses of DAC and in 54% of AML pts after a median of 3 (2-11) courses. Four AML pts receiving standard cytarabine-based induction chemotherapy and four pts with pancreatic cancer receiving gemcitabine-based treatment did not show HbF induction to >1%. When analyzing clinical survival endpoints, elevated baseline HbF was associated with longer median overall survival (OS) for MDS: 26.6 vs. 8.6 months (HR 8.56, 95% CI 1.74-42.49, p=0.008). Similarly, median PFS and AMLFS was prolonged in "HbF high" MDS pts with 15.4 compared to 5.9 months (p=0.016) and 26.3 compared to 8.8 months (p=0.03), respectively. A statistically non-significant trend towards higher HbF baseline values (median 1.5%, range 0.3% to 3.9%) in MDS pts achieving a CR, PR or hematological improvement compared to non-responders (median baseline 0.4%, range 0.1% - 1.9%) was noted. Likewise, OS for AML pts with elevated pre-treatment HbF was prolonged with 10.0 vs. 2.9 months OS (HR 3.01, 95% CI 1.26-7.22, p=0.014). HbF baseline values were comparable in the group that did achieve any response (CR, PR, antileukemic effect) vs. the non-responding group. In a multivariate analysis including LDH and age, the predictive value of HbF was retained. Time-dependent Cox models revealed that the predictive value of treatment-induced HbF induction was markedly inferior to that of baseline HbF. Conclusion: We provide first evidence for in vivo induction of HbF by DAC in MDS and AML pts. Notably, HbF values elevated already prior to treatment harbor highly significant predictive value for survival benefit upon DAC whereas HbF induction is inferior to a stronger effect of pre-treatment HbF. Our findings warrant incorporation of HbF as potential predictive biomarker in larger prospective studies. Disclosures Claus: Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria, Other: Travel Funding. Becker:BMS: Honoraria; Novartis: Honoraria. Lübbert:Ratiopharm: Other: Study drug valproic acid; Janssen-Cilag: Other: Travel Funding, Research Funding; Celgene: Other: Travel Funding.
- Published
- 2016
37. Validation Of a Multi-Diagnostic Approach Including Flow Cytometry To Identify Specific Risk Categories Within Low and Intermediate-1 Risk Myelodysplastic Syndromes Within a Prospective Clinical Trial: A Study On Behalf Of The HOVON89 Study Group
- Author
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Marian Stevens-Kroef, Theresia M. Westers, Georgine E. de Greef, Dana A. Chitu, Saskia K. Klein, Pedro Silva Coelho, Claudia Cali, Pierre W. Wijermans, Canan Alhan, Joop H. Jansen, Arjan A. van de Loosdrecht, Heleen Visser-Wisselaar, Martijn R. Schaafsma, Eline M. P. Cremers, Petra Muus, Gert J. Ossenkoppele, Edo Vellenga, M. Marwijk Kooy, Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Stem Cell Aging Leukemia and Lymphoma (SALL)
- Subjects
Oncology ,medicine.medical_specialty ,Cytopenia ,Myeloid ,business.industry ,Myelodysplastic syndromes ,Immunology ,Cell Biology ,Hematology ,Refractory anemia with ringed sideroblasts ,medicine.disease ,Biochemistry ,Leukemia ,medicine.anatomical_structure ,Dysplasia ,hemic and lymphatic diseases ,Internal medicine ,medicine ,business ,Refractory cytopenia with multilineage dysplasia ,Lenalidomide ,medicine.drug - Abstract
Myelodysplastic syndromes (MDS) constitute a heterogeneous group of hematopoietic stem cell disorders, characterized by ineffective hematopoiesis resulting in cytopenias and variable risk of acute myeloid leukemia (AML). To make an accurate distinction between specific risk categories in MDS, especially in low and intermediate risk MDS, a multi-diagnostic approach is recommended. To verify the efficacy of multiple diagnostic tools in MDS we used the HOVON89 study-cohort (a prospective phase II randomized multicenter study to assess the efficacy of lenalidomide with or without erythropoietin and granulocyte-colony stimulating factor in patients with low-intermediate-1 risk MDS; trial registered at www.trialregister.nl as NTR1825; EudraCT nr.: 2008-002195-10. Inclusion target of the study is 200 low/intermediate-1 risk MDS patients (134 enrolled, inclusion ongoing). We collect data on cytomorphology (CM), conventional cytogenetics (CCG), fluorescence in situ hybridization (FISH) and microarray-based genomic profiling. In addition, we performed flow cytometric (FC) analysis according to European LeukemiaNet guidelines (Van de Loosdrecht et al., Haematologica 2009 and Leukemia 2012). Current CM results (N=98) identified: 8 refractory anemia (RA); 16 refractory anemia with ringed sideroblasts (RARS); 43 refractory cytopenia with multilineage dysplasia with/without ringed sideroblasts (RCMD/RCMD-RS); 16 refractory anemia with excess blast-1 (RAEB-1), 5 chronic myelomonocytic leukemia-1 (CMML-1) and 10 patients with isolated del(5q). CCG analysis (N=101) indicated 2 very good risk, 84 good risk, 13 intermediate risk and 2 poor risk patients according to the IPSS-R risk categories (Greenberg et al., Blood 2012). In addition, interphase FISH analysis (N=72) was normal in 15 patients, in 6 patients the del(5q) was confirmed. From 68 MDS patients data from both CCG and microarray were available. Microarray-based genomic profiling identified genomic abnormalities such as copy neutral loss of heterozygosity and small ( FC analysis (N=82) evaluated aberrancies with regard to count, marker expression level and lineage infidelity marker expression on myeloid progenitors, B cell progenitors, maturing myeloid/monocytic and erythroid cells. Current, validated FC-scoring systems identified 60/81 (Della Porta et al., Haematologica 2012) and 61/81 (Wells et al., Blood 2003) patients with MDS. Both scoring systems do not evaluate dyserytropoiesis and dysmegakaropoiesis, thereby possibly not recognizing RA, RARS or RCMD patients with only dyserytropoiesis and dysmegakaropoiesis. We integrated both scoring systems into one score (Van de Loosdrecht et al., Leukemia 2012, and JNCCN 2013). Patients were divided into 3 categories: not likely MDS (A), signs of dysmyelopoiesis (B) and fitting MDS (C). This score diagnosed 69/78 patients as probably or likely MDS by FC (B or C, figure 1). Remarkably, patients scored as ‘category A’ only displayed dyserytropoiesis and/or dysmegakaryopoiesis by CM. FC identified dyserytropoiesis in these patients, however, a consensus erytroid flow score is not yet validated. In addition, FC identified different risk categories within the patient group with no genetic abnormalities (based on CCG, FISH and microarray-based genomic profiling; data not shown). In conclusion, this is the first prospective study in low/int-1 risk MDS that validates FC as a valuable diagnostic tool in MDS (sensitivity of FC in this cohort: 88%). FC only failed to recognize some patients with only dyserytropoiesis and dysmegakaryopoiesis by CM, not evaluated by the current scoring system. Thirteen patients with unilineage dysplasia by CM had multilineage dysplasia by FC. We postulate that RA/RARS patients with multi-lineage dysplasia by FC may have clinical features of RCMD patients and therefore a higher risk on transformation to AML. Clinical follow-up data are expected within 1.5 year. In near future, a multi-diagnostic approach may i) identify risk categories within well defined IPSS-R subgroups, ii) predict risk on transformation and iii) select patients who might benefit from new emerging drugs for low-int-1 risk MDS. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2013
38. Identification Of Chromosomal Abnormalities By Microarray-Based Genomic Profiling As Compared To Karyotyping In Patients With Low and Intermediate-1 Risk Myelodysplastic Syndromes Within a Prospective Clinical Trial: A Study On Behalf Of The HOVON89 Study Group
- Author
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Saskia K. Klein, Marian Stevens-Kroef, Edo Vellenga, Georgine E. de Greef, Petra Muus, Dana A. Chitu, Heleen A. Visser Wisselaar, Najat El Idrissi-Zaynoun, M. R. Schaafsma, Eline M. P. Cremers, Theresia M. Westers, Annet Simons, Pierre W. Wijermans, Joop H. Jansen, M. van Marwijk Kooy, Gert J. Ossenkoppele, Arjan A. van de Loosdrecht, Bert A. van der Reijden, Canan Alhan, Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Stem Cell Aging Leukemia and Lymphoma (SALL)
- Subjects
medicine.medical_specialty ,medicine.diagnostic_test ,Microarray ,Myelodysplastic syndromes ,Immunology ,Cytogenetics ,Karyotype ,Cell Biology ,Hematology ,Biology ,Bioinformatics ,medicine.disease ,Biochemistry ,Loss of heterozygosity ,Gene expression profiling ,Chromosome abnormality ,medicine ,Fluorescence in situ hybridization - Abstract
Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic disorders, characterized by ineffective hematopoiesis resulting in cytopenias and a highly variable clinical course. Cytogenetics are routinely used as one of the diagnostic, prognostic and therapeutic markers in the clinical management of MDS (Greenberg et al. Blood 120:2454,2012). Although karyotyping is generally considered as the gold standard in the cytogenetic characterization of MDS, 40-60% of the patients exhibit a normal karyotype. Intrinsically, the resolution of karyotyping is limited by its capacity to detect only those copy number changes that are microscopically visible (5-10 Mb in size). In contrast, microarray-based genomic profiling analyses allow a genome-wide detection of copy number alterations (CNAs), down to 100 kb in size, and regions of copy neutral loss of heterozygosity (CNLOH). Such analyses also overcome some of the other major limitations of karyotyping such as low success rate due to inadequate metaphase yield and/or poor banding quality. We have compared karyotyping and fluorescence in situ hybridization (FISH) with microarray-based genomic profiling with respect to the detection yield for genetic abnormalities in bone marrow samples from lower risk MDS patients. We used the HOVON89 study-cohort, a prospective phase II randomized multicenter study to assess the efficacy of lenalidomide with or without erythropoietin and granulocyte-colony stimulating factor in patients with low/intermediate-1 risk MDS; www.trialregister.nl; NTR1825; EudraCT nr.: 2008-002195-10. Inclusion target of the study is 200 low/intermediate-1 risk MDS patients (134 enrolled, inclusion ongoing). Data regarding cytogenetics, FISH and microarray were obtained in a fully blinded fashion for 68 MDS patients. For microarray-based genomic profiling we used the recently launched high resolution CytoScan HD Array (Affymetrix) platform. The following interpretation criteria were applied: (i) the threshold for CNAs was set at >5 Mb, (ii) inclusion of 10 Mb and to telomere. Karyotyping and interphase FISH were performed using standard cytogenetic methods. In all 4 patients where karyotyping revealed no metaphases interphase FISH was performed. Thirty-six of the 68 (53%) MDS patients had an abnormal microarray profile. Of interest, in 13 of these 36 patients no abnormalities were observed by karyotyping and/or FISH. All these abnormalities observed by microarray only, involved focal In conclusion, we demonstrate that in the present cohort of 68 patients, microarray-based genomic profiling allows the identification of almost all copy number abnormalities also observed by karyotyping and FISH. In addition, we show that microarray-based genomic profiling allows the detection of potential prognostic relevant abnormalities (focal CNAs and CNLOH) which would have remained undetected by karyotyping and FISH. The predictive and/or prognostic value of these novel CNAs and CNLOH will be evaluated within the ongoing prospective clinical HOVON89 trial in lower risk MDS. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2013
39. Very Mild Pathology in a Case of Hb S/β˚-Thalassemia in Combination with a Homozygosity for the α-Thalassemia 3.7 kb Deletion
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L. F. Bernini, Pierre W. Wijermans, J. L. Kerkhoffs, H. L. Haak, Piero C. Giordano, P. van Delft, and Cornelis L. Harteveld
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Genetics ,business.industry ,Biochemistry (medical) ,Clinical Biochemistry ,Medicine ,Hematology ,Alpha-thalassemia ,Beta0 Thalassemia ,business ,medicine.disease ,Genetics (clinical) - Published
- 2000
40. Preferential cytogenetic response to continuous intravenous low-dose decitabine (DAC) administration in myelodysplastic syndrome with monosomy 7
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Regina Kunzmann, Björn Rüter, Pierre W. Wijermans, Rainer Claus, and Michael Lübbert
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Chromosome 7 (human) ,Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Low dose ,Decitabine ,Cell Biology ,Hematology ,Biochemistry ,Cytogenetic Response ,Bayesian design ,hemic and lymphatic diseases ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
To the editor: We read with great interest the recent publication by Kantarjian and colleagues addressing the value of different outpatient low-dose decitabine (DAC) schedules in higher-risk myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia.[1][1] By the Bayesian design of that
- Published
- 2007
41. Treatment, patterns of failure, and survival of patients with Stage I nodal and extranodal non-Hodgkin's lymphomas, according to data in the population-based registry of the comprehensive cancer centre west
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Augustinus D.G. Krol, Pierre W. Wijermans, J. Han van Krieken M.D., Hanneke C. Kluin-Nelemans, Jo Hermans, Lilian Dawson, S. Snijder, Evert M. Noordijk, and Philip M. Kluin
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Oncology ,Patterns of failure ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,education.field_of_study ,business.industry ,medicine.medical_treatment ,Population ,Cancer ,medicine.disease ,Surgery ,Non-Hodgkin's lymphoma ,medicine.anatomical_structure ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,Cancer centre ,medicine ,education ,business ,neoplasms ,Population-Based Registry ,Lymph node - Abstract
BACKGROUND Primary extranodal lymphomas (EN-NHLs) are a heterogeneous category of tumors that are considered to be different from primary nodal non-Hodgkin's lymphomas (N-NHLs). To what extent these differences have clinical implications is currently not very clear, because knowledge of EN-NHL as a separate group is limited. METHODS Using data from the Comprehensive Cancer Centre West (CCCW) population-based NHL registry in the Netherlands, N-NHL and EN-NHL patients were compared to determine differences in characteristics at diagnosis, responses to treatment, patterns of failure, and survival. RESULTS At presentation, EN-NHL patients had poorer performance scores and more often bulky tumors compared with N-NHL patients, resulting in poorer responses to treatment (complete response rates were 72% and 84%, respectively; P = 0.04) and inferior 5-year overall survival (49% and 63%, respectively; P = 0.003). Among EN-NHL patients, considerable variations in response, survival, and relapse rates were observed, with gastric NHL patients having the best and central nervous system NHL patients having the worst prognosis (66% and 7% 5-year overall survival, respectively). Relapse rates for N-NHL and EN-NHL patients did not differ (39% and 36% 5-year relapse rates, respectively), whereas among EN-NHL patients considerable differences in relapse rates were noted. Relapses among N-NHL patients were mainly found in nodal sites, whereas recurrent disease in EN-NHL patients was mainly found in extranodal sites. CONCLUSIONS In this population-based study, Stage I EN-NHL patients as a group had a poorer prognosis than N-NHL patients. However, among EN-NHL patients, considerable differences in response, relapse risk, and survival were observed. The failure analysis conducted in this study suggests that patterns of dissemination for N-NHL and EN-NHL are different. Cancer 1998;83:1612-1619. © 1998 American Cancer Society.
- Published
- 1998
42. Liposomal amphotericin B compared with amphotericin B deoxycholate in the treatment of documented and suspected neutropenia-associated invasive fungal infections
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Simon Daenen, Rlh Jansen, H van der Lelie, S. de Marie, Raoul Herbrecht, Henk C. Hoogsteden, Jan J. Cornelissen, W. C. J. Hop, Acap Leenders, Henri A. Verbrugh, Bob Löwenberg, and Pierre W. Wijermans
- Subjects
medicine.medical_specialty ,Leukopenia ,business.industry ,Itraconazole ,Hematology ,Neutropenia ,Aspergillosis ,medicine.disease ,Gastroenterology ,Surgery ,Internal medicine ,Amphotericin B deoxycholate ,Amphotericin B ,Medicine ,medicine.symptom ,business ,Fluconazole ,Mycosis ,medicine.drug - Abstract
It has been suggested that a better outcome of neutropenia-associated invasive fungal infections can be achieved when high doses of lipid formulations of amphotericin B are used. We now report a randomized multicentre study comparing liposomal amphotericin B (AmBisome, 5 mg/kg/d) to amphotericin B deoxycholate (AmB, 1 mg/kg/d) in the treatment of these infections. Of 106 possible patients, 66 were enrolled and analysed for efficacy: nine had documented fungaemia, 17 had other invasive mould infections and 40 had suspected pulmonary aspergillosis. After completion of the course medication, in the AmBisome group (n = 32) 14 patients had achieved complete response, seven a partial response and 11 were failures as compared to 6, 13 and 15 patients (n = 34) treated with AmB (P=0.09); P=0.03 for complete responders. A favourable trend for AmBisome was found at day 14, in patients with documented infections and in patients with pulmonary aspergillosis (P=0.05 and P=0.096 respectively). Mortality rates were lower in patients treated with AmBisome (adjusted for malignancy status, P=0.03). More patients on AmB had a >100% increase of their baseline serum creatinine (P
- Published
- 1998
43. Continuous infusion of low-dose 5-Aza-2′-deoxycytidine in elderly patients with high-risk myelodysplastic syndrome
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Pierre W. Wijermans, Jwm Krulder, Pierre Neve, and Peter C. Huijgens
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Male ,Oncology ,Cancer Research ,Pancytopenia ,medicine.medical_treatment ,Leukocyte Count ,chemistry.chemical_compound ,Bone Marrow ,Infusions, Intravenous ,Aged, 80 and over ,Leukemia, Myelomonocytic, Chronic ,Hematology ,Middle Aged ,Prognosis ,Survival Rate ,Leukemia, Myeloid ,Acute Disease ,Azacitidine ,Female ,Deoxycytidine ,medicine.drug ,Antimetabolites, Antineoplastic ,medicine.medical_specialty ,Anemia ,Decitabine ,Antineoplastic Agents ,Risk Assessment ,Drug Administration Schedule ,Internal medicine ,medicine ,Humans ,Adverse effect ,Survival rate ,Aged ,Chemotherapy ,Anemia, Refractory, with Excess of Blasts ,Platelet Count ,business.industry ,Myelodysplastic syndromes ,Anemia, Refractory ,medicine.disease ,Surgery ,chemistry ,Myelodysplastic Syndromes ,Erythrocyte Count ,Morbidity ,business - Abstract
There is no standard therapy for elderly patients with high-risk myelodysplastic syndrome (MDS). The treatment options of low-dose Ara-C and haematopoietic growth factors are disappointing in regard to response rate or response duration. We tested the treatment with a 72-h continuous infusion of low-dose 5-Aza-2'-deoxycytidine (DAC) in a group of 29 elderly patients with high-risk MDS. In 15 patients (54%) we observed a response. Eight complete responses were reached, even among patients with bad prognostic cytogenetic findings. The actuarial median survival from the start of the therapy was 46 weeks. The only (and major) toxicity was myelosuppression, leading to a prolonged cytopenic period and thus leading to five toxic deaths (17%) in this high-risk patient group. We conclude that DAC is an effective drug in the treatment of MDS patients and that it probably works via its cytotoxic activity. Myelotoxicity is its major adverse effect.
- Published
- 1997
44. The efficiency of therapeutic erythrocytapheresis compared to phlebotomy: a mathematical tool for predicting response in hereditary hemochromatosis, polycythemia vera, and secondary erythrocytosis
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Dorothea, Evers, Jean-Louis, Kerkhoffs, Liane, Van Egmond, Martin R, Schipperus, and Pierre W, Wijermans
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Adult ,Aged, 80 and over ,Male ,Blood Volume ,Mathematical Concepts ,Polycythemia ,Middle Aged ,Models, Theoretical ,Cytapheresis ,Young Adult ,Treatment Outcome ,Hematocrit ,Phlebotomy ,Humans ,Female ,Hemochromatosis ,Polycythemia Vera ,Aged ,Retrospective Studies - Abstract
Recently, therapeutic erythrocytapheresis (TE) was suggested to be more efficient in depletion of red blood cells (RBC) compared to manual phlebotomy in the treatment of hereditary hemochromatosis (HH), polycythemia vera (PV), and secondary erythrocytosis (SE). The efficiency rate (ER) of TE, that is, the increase in RBC depletion achieved with one TE cycle compared to one phlebotomy procedure, can be calculated based on estimated blood volume (BV), preprocedural hematocrit (Hct(B)), and delta-hematocrit (ΔHct). In a retrospective evaluation of 843 TE procedures (in 45 HH, 33 PV, and 40 SE patients) the mean ER was 1.86 ± 0.62 with the highest rates achieved in HH patients. An ER of 1.5 was not reached in 37.9% of all procedures mainly concerning patients with a BV below 4,500 ml. In 12 newly diagnosed homozygous HH patients, the induction phase duration was medially 38.4 weeks (medially 10.5 procedures). During the maintenance treatment of HH, PV, and SE, the interval between TE procedures was medially 13.4 weeks. This mathematical model can help select the proper treatment modality for the individual patient. Especially for patients with a large BV and high achievable ΔHct, TE appears to be more efficient than manual phlebotomy in RBC depletion thereby potentially reducing the numbers of procedures and expanding the interprocedural time period for HH, PV, and SE.
- Published
- 2013
45. Age and organ damage correlate with poor survival in myeloma patients: meta-analysis of 1435 individual patient data from 4 randomized trials
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Sonja Zweegman, Antonio Palumbo, Pierre W. Wijermans, Massimo Offidani, Maria-Victoria Mateos, Albert Oriol, Mario Boccadoro, Maide Cavalli, Bronno van der Holt, Chiara Cerrato, Pieter Sonneveld, Ana Isabel Teruel, Alessandra Larocca, Roberto Marasca, Roberto Ria, Vittorio Montefusco, Juan José Lahuerta, Davide Rossi, Sara Bringhen, Roberto Mina, Antonietta Falcone, Giovannino Ciccone, Vincenzo Callea, Anna Marina Liberati, Martijn R. Schaafsma, Jesús F. San Miguel, Luca Franceschini, Andrea Evangelista, Hematology, and CCA - Innovative therapy
- Subjects
Male ,cancer incidence ,peripheral neuropathy ,Age Factors ,Aged ,Antineoplastic Combined Chemotherapy Protocols ,Cause of Death ,Female ,Humans ,Multiple Myeloma ,Neoplasm Staging ,Prognosis ,Proportional Hazards Models ,Randomized Controlled Trials as Topic ,Treatment Outcome ,retrospective study ,thrombocytopenia ,heart disease ,cancer risk ,law.invention ,Randomized controlled trial ,law ,phase 3 clinical trial (topic) ,cancer survival ,Multiple myeloma ,Cause of death ,progression free survival ,Bortezomib ,disease course ,article ,Hematology ,anemia ,female ,myeloma ,gastrointestinal disease ,medicine.drug ,medicine.medical_specialty ,overall survival ,venous thromboembolism ,male ,Median follow-up ,Internal medicine ,medicine ,follow up ,neutropenia ,human ,second cancer ,Adverse effect ,business.industry ,Proportional hazards model ,medicine.disease ,major clinical study ,infection ,Surgery ,Thalidomide ,Original Articles and Brief Reports ,business ,meta analysis - Abstract
This is an open-access paper.-- et al., Thalidomide and bortezomib are extensively used to treat elderly myeloma patients. In these patients, treatmentrelated side effects are frequent and full drug doses difficult to tolerate. We retrospectively analyzed data from 1435 elderly patients enrolled in 4 European phase III trials including thalidomide and/or bortezomib. After a median follow up of 33 months (95%CI: 10-56 months), 513 of 1435 patients (36%) died; median overall survival was 50 months (95%CI: 46-60 months). The risk of death was increased in patients aged 75 years or over (HR 1.44, 95%CI: 1.20-1.72; P
- Published
- 2013
46. An IVS1-116 (A→G) acceptor splice site mutation in the α2 globin gene causing α+ thalassaemia in two Dutch families
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Monique Losekoot, Pierre W. Wijermans, H. L. Haak, C. L. Harteveld, Peter Van Delft, Luigi F. Bernini, D. Batelaan, Piero C. Giordano, and J. G. A. M. Heister
- Subjects
Genetics ,Splice site mutation ,Sequence Analysis, RNA ,Sequence analysis ,RNA Splicing ,Nonsense mutation ,Intron ,DNA ,Sequence Analysis, DNA ,Hematology ,Biology ,Polymerase Chain Reaction ,Molecular biology ,Stop codon ,Globins ,Pedigree ,Blotting, Southern ,alpha-Thalassemia ,Mutation ,Consensus sequence ,Humans ,RNA ,splice ,Globin - Abstract
We report the characterization of an alpha +(-)thalassaemia determinant due to a transition A-->G of the acceptor splice consensus site sequence (IVS1-116) of the first intron of the alpha 2-globin gene. The mutation, found in two apparently unrelated Dutch Caucasian families, was detected by DGGE analysis followed by direct sequencing. Haplotype analysis suggests a common origin of the mutation in both families. The disruption of the acceptor splice site consensus sequence interferes with the correct splicing and leads to the retention of the first intron in the abnormally spliced mRNA. The alpha +(-)thalassaemia phenotype observed in the carriers is caused by the absence of functional mRNA which cannot be replaced by the abnormally spliced mRNA. The low amounts of abnormal mRNA found in reticulocytes is, most probably, due to the post-transcriptional instability which follows the presence of a termination codon in the retained intronic sequence. This situation is often associated with a decreased mRNA stability as observed for several nonsense mutations of the beta-globin gene.
- Published
- 1996
47. Addition of bevacizumab to chemotherapy in acute myeloid leukemia at older age: a randomized phase 2 trial of the Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and the Swiss Group for Clinical Cancer Research (SAKK)
- Author
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Okke de Weerdt, Dimitri Breems, Bob Löwenberg, Mark-David Levin, Edo Vellenga, August Ferrant, Georg Stussi, Mels Hoogendoorn, Harry C. Schouten, Kees van Montfort, Rene Hollestein, Constantijn J.M. Halkes, Georgine E. de Greef, Yvette van Norden, Johan Maertens, Marinus van Marwijk Kooij, Gregor Verhoef, Mojca Jongen-Lavrencic, Bart J. Biemond, Gert J. Ossenkoppele, Pierre W. Wijermans, Arjan A. van de Loosdrecht, Jakob Passweg, Carlos Graux, Thomas Pabst, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Stem Cell Aging Leukemia and Lymphoma (SALL), Interne Geneeskunde, RS: GROW - School for Oncology and Reproduction, Amsterdam institute for Infection and Immunity, Cancer Center Amsterdam, Clinical Haematology, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service d'hématologie, UCL - (SLuc) Service d'hématologie, Internal Medicine, Hematology, Erasmus MC other, Cardiology, and CCA - Innovative therapy
- Subjects
Oncology ,Male ,Biomedical Research ,Time Factors ,genetic structures ,medicine.medical_treatment ,International Cooperation ,Phases of clinical research ,Biochemistry ,ANGIOGENESIS ,0302 clinical medicine ,Belgium ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Netherlands ,Aged, 80 and over ,0303 health sciences ,education.field_of_study ,Remission Induction ,Myeloid leukemia ,Hematology ,Middle Aged ,3. Good health ,Bevacizumab ,medicine.anatomical_structure ,Treatment Outcome ,Leukemia, Myeloid ,030220 oncology & carcinogenesis ,Hematologic Neoplasms ,Acute Disease ,Female ,Switzerland ,medicine.drug ,medicine.medical_specialty ,BONE-MARROW ,Immunology ,Population ,Antibodies, Monoclonal, Humanized ,Disease-Free Survival ,Drug Administration Schedule ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Internal medicine ,Humans ,education ,Adverse effect ,030304 developmental biology ,Aged ,Chemotherapy ,business.industry ,Cell Biology ,Length of Stay ,ENDOTHELIAL GROWTH-FACTOR ,Cytarabine ,Bone marrow ,business - Abstract
An urgent need for new treatment modalities is emerging in elderly patients with acute myeloid leukemia (AML). We hypothesized that targeting VEGF might furnish an effective treatment modality in this population. Elderly patients with AML were randomly assigned in this phase 2 study (n = 171) to receive standard chemotherapy (3 + 7) with or without bevacizumab at a dose of 10 mg/kg intravenously at days 1 and 15. In the second cycle, patients received cytarabine 1000 mg/m2 twice daily on days 1-6 with or without bevacizumab. The complete remission rates in the 2 arms were not different (65%). Event-free survival at 12 months was 33% for the standard arm versus 30% for the bevacizumab arm; at 24 months, it was 22% and 16%, respectively (P = .42). The frequencies of severe adverse events (SAEs) were higher in the bevacizumab arm (n = 63) compared with the control arm (n = 28; P = .043), but the percentages of death or life-threatening SAEs were lower in the bevacizumab arm (60% vs 75% of SAEs). The results of the present study show that the addition of bevacizumab to standard chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR904 in The Nederlands Trial Register (www.trialregister.nl).
- Published
- 2012
48. Is hyperhomocysteinaemia a risk factor for recurrent venous thrombosis?
- Author
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Pierre W. Wijermans, W. B. J. Gerrits, M. den Heijer, Henk J. Blom, H.L. Haak, Gerard M. J. Bos, and Frits R. Rosendaal
- Subjects
Adult ,Male ,Percentile ,medicine.medical_specialty ,Homocysteine ,Population ,Gastroenterology ,chemistry.chemical_compound ,Methionine ,Recurrence ,Risk Factors ,Internal medicine ,Humans ,Medicine ,Risk factor ,education ,Vein ,Aged ,Aged, 80 and over ,education.field_of_study ,business.industry ,Fasting ,General Medicine ,Odds ratio ,Middle Aged ,Thrombophlebitis ,medicine.disease ,Thrombosis ,Venous thrombosis ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Female ,business - Abstract
Several studies have shown a relation between hyperhomocysteinaemia and arterial vascular disease. We looked at the association between hyperhomocysteinaemia and venous thrombosis which could be clinically important as hyperhomocysteinaemia is easily corrected by vitamin supplementation. We studied 185 patients with a history of recurrent venous thrombosis and 220 controls from the general population. Homocysteine concentrations were measured before and 6 h after oral methionine loading. We defined hyperhomocysteinaemia as the homocysteine concentration above the fasting or the postmethionine value found for the 90th percentile of the controls. Of the 185 patients with recurrent thrombosis, 46 (25%) had fasting homocysteine concentrations above the 90th percentile or the controls (odds ratio is 3·1 [1·8-5·5]). After adjustment for age, sex, and menopausal status the odds ratio was 2·0 (1·5-2·7). Similar results were found for the post-methionine value (unadjusted odds ratio 3·1 [1·7-5·5], adjusted 2·6 [1·9-3·5]). Hyperhomocysteinaemia is a common risk factor for recurrent venous thrombosis and can lead to a two-fold or three-fold increase in risk.
- Published
- 1995
49. A novel 7·9 kb deletion causing α+ -thalassaemia in two independent families of Indian origin
- Author
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Cornelis L. Harteveld, Monique Losekoot, M. C. Kappers-Klunne, Jitske Weegenaar, Piero C. Giordano, Peter Van Delft, and Pierre W. Wijermans
- Subjects
Hemolytic anemia ,Genetics ,Mutation ,Alu element ,Hematology ,Biology ,medicine.disease_cause ,medicine.disease ,Molecular biology ,Phenotype ,hemic and lymphatic diseases ,medicine ,Homologous chromosome ,Globin ,Gene ,Recombination - Abstract
Summary. We describe the characterization of a novel 7·9 kb deletion that eliminated one of the duplicated α-globin genes, causing an α+-thalassaemia phenotype in two independent carriers of Suriname–Indian origin. The molecular characterization of the deletion breakpoint fragment revealed neither involvement of Alu repeat sequences nor the presence of homologous regions prone to recombination, suggesting a non-homologous recombination event. This α+-thalassaemia deletion was found to give rise to an atypical haemoglobin H (HbH) disease characterized by a non-transfusion-dependent moderate microcytic hypochromic anaemia in combination with a poly adenylation signal mutation of the α-globin gene (α2 AATAAA AATA-- --).
- Published
- 2003
50. [Demethylating medication in myelodysplastic syndrome]
- Author
-
Martijn L, Manson, Ellen J B, Derissen, Pierre W, Wijermans, Jan H M, Schellens, and Jos H, Beijnen
- Subjects
Antimetabolites, Antineoplastic ,Treatment Outcome ,Myelodysplastic Syndromes ,Age Factors ,Azacitidine ,Humans ,DNA Methylation ,Decitabine ,DNA Modification Methylases - Abstract
Myelodysplastic syndrome, a disorder of haematopoiesis, is associated with anaemia and an increased risk of infections, bleeding and the development of acute myeloid leukaemia. The disorder occurs mainly in later life. Until recently the only therapy that could induce sustained remission was allogeneic stem cell transplantation. However in elderly patients caution is needed with this therapy. Increasing awareness of the role of epigenetic changes in cancer development has led to the rediscovery of the cytidine analogues azacitidine and decitabine. At low doses these drugs inhibit DNA methylation. The efficacy of these drugs was demonstrated in the treatment of patients with myelodysplastic syndrome. These drugs showed low toxicity and were relatively well-tolerated in elderly patients. The results with azacitidine and decitabine have demonstrated that manipulation of the epigenetic process offers new antineoplastic treatment options.
- Published
- 2012
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