Theo de Witte

Publications (84)621.43 Total impact

• Source

  Available from: Argiris Symeonidis

  Article: Allogeneic stem cell transplantation for myelodysplastic syndromes with bone marrow fibrosis.

  Nicolaus Kröger, Tatjana Zabelina, Anja van Biezen, Ronald Brand, Dietger Niederwieser, Rodrigo Martino, Zi Yi Lim, Francesco Onida, Christoph Schmid, Laurent Garderet, Marie Robin, Michael van Gelder, Reinhard Marks, Argiris Symeonidis, Guido Kobbe, Theo de Witte
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  ABSTRACT: Bone marrow fibrosis in patients with myelodysplastic syndrome is associated with a poor outcome, but whether the outcome after allogeneic stem cell transplantation is related to the degree of bone marrow fibrosis is unknown. Patients with myelodysplastic syndrome and known bone marrow histology (n=721) who underwent hematopoietic stem cell transplantation were classified according to the degree of bone marrow fibrosis into those without fibrosis (n=483), those with mild or moderate fibrosis (n=199) and those with severe fibrosis (n=39) and analyzed regarding engraftment, treatment-related mortality, relapse and survival. The degree of fibrosis was not associated with disease status or abnormal cytogenetics. The cumulative incidence of engraftment achieved at day +30 in non-fibrotic patients was 93% and was significantly lower in those with mild or moderate fibrosis (89%) and severe fibrosis (75%) (P=0.009). Neutrophil engraftment occurred later in patients with mild or moderate fibrosis and severe fibrosis than in patients without fibrosis (median 17 versus 20 versus 16 days, respectively; P=0.002). The cumulative incidence of relapse at 3 years was significantly higher in patients with severe fibrosis than in those with a lesser degree of fibrosis or no fibrosis (47% versus 28% versus 27%, respectively; P=0.04), resulting in comparable 3-year disease-free survival rates in patients without fibrosis and in those with mild or moderate fibrosis (42% versus 38%, respectively) but a lower disease-free survival rate in those with severe fibrosis (18%; P=0.002). Severe fibrosis remained an independent factor for reduced survival (hazard ratio, 1.9; P=0.006). Among patients with myelodysplastic syndromes, only severe fibrosis affects survival after hematopoietic stem cell transplantation while patients with mild or moderate fibrosis have an outcome comparable to that of patients without bone marrow fibrosis.
  Haematologica 10/2010; 96(2):291-7. · 6.42 Impact Factor
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  Available from: Stefan Suciu

  Article: 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.

  Theo de Witte, Anne Hagemeijer, Stefan Suciu, Amin Belhabri, Michel Delforge, Guido Kobbe, Dominik Selleslag, Harry C Schouten, Augustin Ferrant, Harald Biersack, Sergio Amadori, Petra Muus, Joop H Jansen, Eva Hellström-Lindberg, Tibor Kovacsovics, Pierre Wijermans, Gert Ossenkoppele, Alois Gratwohl, Jean-Pierre Marie, Roel Willemze
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  ABSTRACT: 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. 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. 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. 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.
  Haematologica 10/2010; 95(10):1754-61. · 6.42 Impact Factor
• Article: Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes.

  Gorica Nikoloski, Saskia M C Langemeijer, Roland P Kuiper, Ruth Knops, Marion Massop, Evelyn R L T M Tönnissen, Adrian van der Heijden, Theresia N Scheele, Peter Vandenberghe, Theo de Witte, Bert A van der Reijden, Joop H Jansen
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  ABSTRACT: In myelodysplastic syndromes (MDS), deletions of chromosome 7 or 7q are common and correlate with a poor prognosis. The relevant genes on chromosome 7 are unknown. We report here that EZH2, located at 7q36.1, is frequently targeted in MDS. Analysis of EZH2 deletions, missense and frameshift mutations strongly suggests that EZH2 is a tumor suppressor. As EZH2 functions as a histone methyltransferase, abnormal histone modification may contribute to epigenetic deregulation in MDS.
  Nature Genetics 08/2010; 42(8):665-7. · 35.53 Impact Factor
• Article: Dexamethasone compared to prednisolone for adults with acute lymphoblastic leukemia or lymphoblastic lymphoma: final results of the ALL-4 randomized, phase III trial of the EORTC Leukemia Group.

  Boris Labar, Stefan Suciu, Roel Willemze, Petra Muus, Jean-Pierre Marie, Georges Fillet, Zwi Berneman, Branimir Jaksic, Walter Feremans, Dominique Bron, Harm Sinnige, Martin Mistrik, Gerard Vreugdenhil, Robrecht De Bock, Damir Nemet, Caroline Gilotay, Sergio Amadori, Theo de Witte
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  ABSTRACT: Corticosteroids are a standard component of the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma. Our aim was to determine whether dexamethasone results in a better outcome than prednisolone. Adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma were randomized to receive, as part of their induction therapy on days 1-8 and 15-22, either dexamethasone 8 mg/m(2) or prednisolone 60 mg/m(2). Those who reached complete remission were given two courses of consolidation therapy with high-dose cytarabine and mitoxantrone and methotrexate and asparaginase. Subsequently patients younger than 50 years, with a suitable donor, were to undergo allogeneic stem cell transplantation, whereas the others were planned to receive either an autologous stem cell transplant or high-dose maintenance chemotherapy with prophylactic central nervous system irradiation. Randomization was done with a minimization technique. The primary endpoint was event-free survival and the analyses was conducted on an intention-to-treat basis. Between August 1995 and October 2003, 325 patients between 15 to 72 years of age were randomized to receive either dexamethasone (163 patients) or prednisolone (162 patients). After induction and the course of first consolidation therapy, 131 (80.4%) patients in the dexamethasone group and 124 (76.5%) in the prednisolone group achieved complete remission. No significant difference was observed between the two treatment groups with regards to 6-year event-free survival rates (+/-SE) which were 25.9% (3.6%) and 28.7% (3.5%) in the dexamethasone and prednisolone groups, respectively (P=0.82, hazard ratio 0.97; 95% confidence interval, 0.75-1.25). Disease-free survival after complete remission was also similar in the dexamethasone and prednisolone groups, the 6-year rates being 32.3% and 37.5%, respectively (hazard ratio 1.03; 95% confidence interval 0.76-1.40). The 6-year cumulative incidences of relapse were 49.8% and 53.5% (Gray's test: P=0.30) while the 6-year cumulative incidences of death were 18% and 9% (Gray's test: P=0.07). In the ALL-4 trial in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma, treatment with dexamethasone did not show any advantage over treatment with prednisolone.
  Haematologica 04/2010; 95(9):1489-95. · 6.42 Impact Factor
• Article: Randomized trial of two schedules of low-dose gemtuzumab ozogamicin as induction monotherapy for newly diagnosed acute myeloid leukaemia in older patients not considered candidates for intensive chemotherapy. A phase II study of the EORTC and GIMEMA leukaemia groups (AML-19).

  Sergio Amadori, Stefan Suciu, Dominik Selleslag, Roberto Stasi, Giuliana Alimena, Liliana Baila, Vittorio Rizzoli, Erika Borlenghi, Gianluca Gaidano, Domenico Magro, Giuseppe Torelli, Petra Muus, Adriano Venditti, Emma Cacciola, Francesco Lauria, Marco Vignetti, Theo de Witte
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  ABSTRACT: This study compared two schedules of low-dose gemtuzumab ozogamicin (GO) as induction monotherapy for untreated acute myeloid leukaemia in older patients unfit for intensive chemotherapy, to identify the more promising regimen for further study. Patients were randomized to receive either best supportive care or a course of GO according to one of two schedules: 3 mg/m(2) on days 1, 3 and 5 (arm A), or GO 6 mg/m(2) on day 1 and 3 mg/m(2) on day 8 (arm B). Primary endpoint was the rate of disease non-progression (DnP), defined as the proportion of patients either achieving a response or maintaining a stable disease following GO induction in each arm. Fifty-six patients were randomized in the two GO arms (A, n = 29; B, n = 27). The rate of DnP was 38% [90% confidence interval (CI), 23-55] in arm A, and 63% (90% CI, 45-78) in arm B. Peripheral cytopenias were the most common adverse events for both regimens. The all-cause early mortality rate was 14% in arm A and 11% in arm B. The day 1 + 8 schedule, which was associated with the highest rate of DnP, met the statistical criteria to be selected as the preferred regimen for phase III comparison with best supportive care.
  British Journal of Haematology 03/2010; 149(3):376-82. · 4.94 Impact Factor
• Source

  Available from: Jean Norden

  Article: Impact of genomic risk factors on outcome after hematopoietic stem cell transplantation for patients with chronic myeloid leukemia.

  Anne M Dickinson, Kim F Pearce, Jean Norden, Stephen G O'Brien, Ernst Holler, Heike Bickeböller, Yesilda Balavarca, Vanderson Rocha, Hans-Jochem Kolb, Ilona Hromadnikova, Petr Sedlacek, Dietger Niederwieser, Ronald Brand, Tapani Ruutu, Jane Apperley, Richard Szydlo, Els Goulmy, Wolfgang Siegert, Theo de Witte, Alois Gratwohl
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  ABSTRACT: Non-HLA gene polymorphisms have been shown to influence outcome after allogeneic hematopoietic stem cell transplantation. Results were derived from heterogeneous, small populations and their value remains a matter of debate. In this study, we assessed the effect of single nucleotide polymorphisms in genes for interleukin 1 receptor antagonist (IL1RN), interleukin 4 (IL4), interleukin 6 (IL6), interleukin 10 (IL10), interferon (IFNG), tumor necrosis factor (TNF) and the cell surface receptors tumor necrosis factor receptor II (TNFRSFIB), vitamin D receptor (VDR) and estrogen receptor alpha (ESR1) in a homogeneous cohort of 228 HLA identical sibling transplants for chronic myeloid leukemia. Three good predictors of overall survival, identified via statistical methods including Cox regression analysis, were investigated for their effects on transplant-related mortality and relapse. Predictive power was assessed after integration into the established European Group for Blood and Marrow Transplantation (EBMT) risk score. Absence of patient TNFRSFIB 196R, absence of donor IL10 ATA/ACC and presence of donor IL1RN allele 2 genotypes were associated with increased transplantation-related mortality and decreased survival. Application of prediction error and concordance index statistics gave evidence that integration improved the EBMT risk score. Non-HLA genotypes were associated with survival after allogeneic hematopoietic stem cell transplantation. When three genetic polymorphisms were added into the EBMT risk model they improved the goodness of fit. Non-HLA genotyping could, therefore, be used to improve donor selection algorithms and risk assessment prior to allogeneic hematopoietic stem cell transplantation.
  Haematologica 03/2010; 95(6):922-7. · 6.42 Impact Factor
• Source

  Available from: PubMed Central

  Article: Hematopoietic stem cells exhibit a specific ABC transporter gene expression profile clearly distinct from other stem cells.

  Leilei Tang, Saskia M Bergevoet, Christian Gilissen, Theo de Witte, Joop H Jansen, Bert A van der Reijden, Reinier A P Raymakers
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  ABSTRACT: ATP-binding cassette (ABC) transporters protect cells against unrelated (toxic) substances by pumping them across cell membranes. Earlier we showed that many ABC transporters are highly expressed in hematopoietic stem cells (HSCs) compared to more committed progenitor cells. The ABC transporter expression signature may guarantee lifelong protection of HSCs but may also preserve stem cell integrity by extrusion of agents that trigger their differentiation. Here we have studied whether non-hematopoietic stem cells (non-HSCs) exhibit a similar ABC transporter expression signature as HSCs. ABC transporter expression profiles were determined in non-hematopoietic stem cells (non-HSCs) from embryonic, neonatal and adult origin as well as in various mature blood cell types. Over 11,000 individual ABC transporter expression values were generated by Taqman Low Density Arrays (TLDA) to obtain a sensitivity comparable with quantitative real-time polymerase chain reactions. We found that the vast majority of transporters are significantly higher expressed in HSCs compared to non-HSCs. Furthermore, regardless their origin, non-HSCs exhibited strikingly similar ABC transporter expression profiles that were distinct from those in HSCs. Yet, sets of transporters characteristic for different stem cell types could be identified, suggesting restricted functions in stem cell physiology. Remarkably, in HSCs we could not pinpoint any single transporter expressed at an evidently elevated level when compared to all the mature blood cell types studied. These findings challenge the concept that individual ABC transporters are implicated in maintaining stem cell integrity. Instead, a distinct ABC transporter expression signature may be essential for stem cell function. The high expression of specific transporters in non-HSCs and mature blood cells suggests a specialized, cell type dependent function and warrants further functional experiments to determine their exact roles in cellular (patho)physiology.
  BMC Pharmacology 01/2010; 10:12.
• Article: Unrelated stem cell transplantation after reduced intensity conditioning for patients with multiple myeloma relapsing after autologous transplantation.

  Nicolaus Kröger, Avichai Shimoni, Georgia Schilling, Rainer Schwerdtfeger, Martin Bornhäuser, Arnon Nagler, Axel R Zander, Marion Heinzelmann, Ronald Brand, Gösta Gahrton, Curly Morris, Dietger Niederwieser, Theo de Witte
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  ABSTRACT: From 2002 to 2007, 49 myeloma patients who relapsed following autologous SCT were included in a prospective multicenter trial to determine the efficacy of a reduced melphalan/fludarabine regimen followed by allogeneic SCT from unrelated donors. All patients showed leucocyte and platelet engraftment after a median of 15 and 19 d, respectively. Grade II-IV acute graft-versus-host disease (GvHD) occurred in 25% of patients and 35% had chronic GvHD. Overall response rate at day 100 was 95% including 46% complete remission (CR). Cumulative incidence of non-relapse mortality at 1 year was 25% [95% confidence interval (CI): 13-37%] and was significantly lower for human leucocyte antigen (HLA)-matched compared to -mismatched SCT (10% vs. 53%, P = 0.001). The cumulative incidence of relapse at 3 years was 55% (95% CI: 40-70%). After a median follow up of 43 months, the estimated 5-year progression-free and overall survival rates were 20% and 26% respectively and were significantly better for matched in CR at day 100 (41% vs. 7%, P = 0.04 and 56% vs. 16%, P = 0.02). We conclude that optimal donor selection is mandatory for a low non-relapse mortality and high relapse incidence, which remains a major concern, should be improved by including post-transplant strategies to upgrade remission status.
  British Journal of Haematology 11/2009; 148(2):323-31. · 4.94 Impact Factor
• Article: Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute myeloid leukemia: the EORTC and GIMEMA Groups Study AML-10.

  Franco Mandelli, Marco Vignetti, Stefan Suciu, Roberto Stasi, Maria-Concetta Petti, Giovanna Meloni, Petra Muus, Filippo Marmont, Jean-Pierre Marie, Boris Labar, Xavier Thomas, Francesco Di Raimondo, Roel Willemze, Vincenzo Liso, Felicetto Ferrara, Liliana Baila, Paola Fazi, Robert Zittoun, Sergio Amadori, Theo de Witte
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  ABSTRACT: To compare the antitumor efficacy of three different anthracyclines in combination with cytarabine and etoposide in adult patients with newly diagnosed acute myeloid leukemia (AML). We randomly assigned 2,157 patients (age range, 15 to 60 years) to receive intensive induction-consolidation chemotherapy containing either daunorubicin, idarubicin, or mitoxantrone. After achieving complete remission (CR), patients were assigned to undergo either allogeneic or autologous stem-cell transplantation (SCT), depending on the availability of a sibling donor. The overall CR rate (69%) was similar in the three groups. Autologous SCT was performed in 37% of cases in the daunorubicin arm versus only 29% and 31% in mitoxantrone and idarubicin, respectively (P < .001). However, the disease-free survival (DFS) and survival from CR were significantly shorter in the daunorubicin arm: the 5-year DFS was 29% versus 37% and 37% in mitoxantrone and idarubicin, respectively. The proportion of patients who underwent allogeneic SCT (22%) was equivalent in the three treatment groups, and the outcome was similar as well. The [corrected] 5-year overall survival rates were 31%, 34%, and 34%, [corrected] respectively. In adult patients with AML who do not receive an allogeneic SCT, the use of mitoxantrone or idarubicin instead of daunorubicin enhances the long-term efficacy of chemotherapy.
  Journal of Clinical Oncology 10/2009; 27(32):5397-403. · 18.37 Impact Factor
• Article: Partial T cell-depleted allogeneic stem cell transplantation following reduced-intensity conditioning creates a platform for immunotherapy with donor lymphocyte infusion and recipient dendritic cell vaccination in multiple myeloma.

  Henriëtte Levenga, Nicolaas Schaap, Frans Maas, Bennie Esendam, Hanny Fredrix, Annelies Greupink-Draaisma, Theo de Witte, Harry Dolstra, Reinier Raymakers
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  ABSTRACT: Allogeneic stem cell transplantation (SCT) in multiple myeloma (MM) may induce a curative graft-versus-myeloma (GVM) effect. Major drawback in unmanipulated reduced-intensity conditioning (RIC) SCT is the risk of severe and longstanding graft-versus-host-disease (GVHD). This study demonstrates that transplantation with a partial T cell-depleted graft creates a platform for boosting GVM immunity by preemptive donor lymphocyte infusion (DLI) and recipient dendritic cell (DC) vaccination, with limited GVHD. All 20MM patients engrafted successfully. Chimerism analysis in 19 patients evaluable at 3 months revealed that 7 patients were complete donor, whereas 12 patients were mixed chimeric. Grade II acute GVHD (aGVHD) occurred in 7 patients (35%) and only 4 patients (21%) developed chronic GVHD (cGVHD). Fourteen patients received posttransplantation immunotherapy, 8 preemptive DLI, 5 patients both DLI and DC vaccination, and 1 patient DC vaccination only. DC vaccination was associated with limited toxicity, and none of these patients developed GVHD. Importantly, overall treatment-related mortality (TRM) at 1 year was low (10%). Moreover, the overall survival (OS) is 84% with median follow-up of 27 months, and none of the patients died from progressive disease. These findings illustrate that this novel approach is associated with limited GVHD and mortality, thus creating an ideal platform for adjuvant immunotherapy.
  Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 10/2009; 16(3):320-32. · 3.15 Impact Factor
• Article: The influence of HLA‐matched sibling donor availability on treatment outcome for patients with AML: an analysis of the AML 8A study of the EORTC Leukaemia Cooperative Group and GIMEMA

  SUSAN KEATING, THEO DE WITTE, STEFAN SUCIU, ROEL WILLEMZE, MARCEL HAYAT, BORIS LABAR, LUIGI RESEGOTTI, PIERLUIGI ROSSI FERRINI, FRANCESCO CARONIA, MURIELLE DARDENNE, GABRIEL SOLBU, MARIA CONCETTA PETTI, MARIA LUCE VEGNA, FRANCO MANDELLI, ROBERT A. ZITTOUN
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  ABSTRACT: To determine whether patients with a HLA-identical sibling donor have a better outcome than patients without a donor, an analysis on the basis of intention-to-treat principles was performed within the framework of the EORTC-GIMEMA randomized phase III AML 8A trial. Patients in complete remission (CR) received one intensive consolidation course. Patients with a histocompatible sibling donor were then allocated allogeneic bone marrow transplantation (alloBMT), the patients without a donor were randomized between autologous BMT (ABMT) and a second intensive consolidation (IC2). 831 patients <46 years old and alive >8 weeks from diagnosis were included. HLA typing was performed in 672 patients. AlloBMT was performed during CR1 in 180 (61%) out of 295 patients with a donor. Another 38 patients were allografted: five in resistant disease, 14 during relapse and 19 in CR2. ABMT was performed in 130 (34%) out of 377 patients without a donor in CR1, in six (2%) patients during relapse and in 38 (10%) patients during CR2. The disease-free survival (DFS) from CR for patients with a donor was significantly longer than for patients without a donor (46% v 33% at 6 years; P = 0.01, RR 0.78, 95% confidence interval 0.63–0.96). The overall survival from diagnosis for patients with a donor was longer, but not statistically significant, than for patients without a donor (48% v 40% at 6 years; logrank P = 0.24). When patients were stratified according to prognostic risk groups, the same trend in favour of patients with a donor was seen for survival duration and the DFS remained significantly longer for this group of patients.
  British Journal of Haematology 09/2009; 102(5):1344 - 1353. · 4.94 Impact Factor
• Article: Risk score for outcome after allogeneic hematopoietic stem cell transplantation: a retrospective analysis.

  Alois Gratwohl, Martin Stern, Ronald Brand, Jane Apperley, Helen Baldomero, Theo de Witte, Giorgio Dini, Vanderson Rocha, Jakob Passweg, Anna Sureda, André Tichelli, Dietger Niederwieser
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  ABSTRACT: It was investigated whether the European Group for Blood and Marrow Transplantation risk score, previously established for chronic myeloid leukemia, could be used to predict outcome after allogeneic hematopoietic stem cell transplantation (HSCT) for hematological disease in general. Age of patient, disease stage, time interval from diagnosis to transplant, donor type, and donor-recipient sex combination were used to establish a score from 0 to 7 points. Its validity was tested in 56,505 patients, 33,113 (58%) male, 23,392 female, median age 33 years (range, 0.5-77 years), with an allogeneic HSCT for a hematological disorder between 1980 and 2005. Survival probability at 5 years decreased from 71% (95% confidence interval [CI], 69%-73%) for risk score 0 for the whole cohort (75%, 95% CI, 72%-78% for the most recent time cohort) to 24% (95% CI, 21%-27% for risk score 6 and 7; 25%, 95% CI, 22%-29% most recent cohort). Transplant-related mortality increased from 15% (95% CI, 14%-17%) for risk score 0 (11%, 95% CI, 9%-13%, most recent cohort) to 47% with risk score 6 and 7 (95% CI, 44%-50%) for the whole cohort (45%, 95% CI, 42%-48%, most recent cohort). The risk score was predictive in all disease categories, over all time periods, and was not altered by transplant techniques. Five well-defined pretransplant patient and donor characteristics give a reasonable risk estimate of allogeneic HSCT. This risk score can provide a basis for the decision between transplant and nontransplant strategies.
  Cancer 08/2009; 115(20):4715-26. · 4.77 Impact Factor
• Article: Acquired mutations in TET2 are common in myelodysplastic syndromes.

  Saskia M C Langemeijer, Roland P Kuiper, Marieke Berends, Ruth Knops, Mariam G Aslanyan, Marion Massop, Ellen Stevens-Linders, Patricia van Hoogen, Ad Geurts van Kessel, Reinier A P Raymakers, Eveline J Kamping, Gregor E Verhoef, Estelle Verburgh, Anne Hagemeijer, Peter Vandenberghe, Theo de Witte, Bert A van der Reijden, Joop H Jansen
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  ABSTRACT: Myelodysplastic syndromes (MDS) represent a heterogeneous group of neoplastic hematopoietic disorders. Several recurrent chromosomal aberrations have been associated with MDS, but the genes affected have remained largely unknown. To identify relevant genetic lesions involved in the pathogenesis of MDS, we conducted SNP array-based genomic profiling and genomic sequencing in 102 individuals with MDS and identified acquired deletions and missense and nonsense mutations in the TET2 gene in 26% of these individuals. Using allele-specific assays, we detected TET2 mutations in most of the bone marrow cells (median 96%). In addition, the mutations were encountered in various lineages of differentiation including CD34(+) progenitor cells, suggesting that TET2 mutations occur early during disease evolution. In healthy tissues, TET2 expression was shown to be elevated in hematopoietic cells with highest expression in granulocytes, in line with a function in myelopoiesis. We conclude that TET2 is the most frequently mutated gene in MDS known so far.
  Nature Genetics 08/2009; 41(7):838-42. · 35.53 Impact Factor
• Article: Higher incidence of relapse with peripheral blood rather than marrow as a source of stem cells in adults with acute myelocytic leukemia autografted during the first remission.

  Norbert-Claude Gorin, Myriam Labopin, Didier Blaise, Josy Reiffers, Giovanna Meloni, Mauricette Michallet, Theo de Witte, Michel Attal, Bernard Rio, Francois Witz, Loic Fouillard, Roel Willemze, Vanderson Rocha
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  ABSTRACT: The cell source for autologous stem cell transplantation has shifted from bone marrow (BM) to peripheral blood (PB). In acute myelocytic leukemia (AML), for patients who receive transplants during first complete remission (CR1), no prospective randomized study has compared relapse incidence (RI) to cell source. We analyzed 2,165 patients who received autografts (1,607 PB and 558 BM) from 1994 to 2006 and were reported to the European Cooperative Group for Blood and Marrow Transplantation with complete research data. Relative to the time of CR1, PB transplants were performed earlier than BM transplants. Because a poorer outcome was associated with a shorter interval from CR1 to transplantation, patients were divided into three groups: BM, early PB (< or = 80 days after CR1), and late PB (> 80 days after CR1) transplantation. In a multivariate analysis adjusted for differences between groups and center, RI was higher with both early PB (56% +/- 3%; hazard ratio [HR], 1.45; 95% CI, 1.11 to 1.9; P = .006) and late PB transplantation (46% +/- 2%; HR, 1.3; 95% CI, 1.06 to 1.59; P = .01) as compared with BM transplantation (39% +/- 2%). This translated into a significantly worse leukemia-free survival (LFS) for early PB transplantation (36% +/- 3%; HR, 0.75; 95% CI, 0.58 to 0.96; P = .02) and a trend for a poorer LFS for late PB (46% +/- 2%; HR, 0.84; 95% CI, 0.7 to 1.01; P = .06) as compared with BM (52% +/- 2%). For patients with AML in CR1, risk of relapse is greater with PB transplantation rather than BM, independent of the interval from CR1 to transplantation.
  Journal of Clinical Oncology 08/2009; 27(24):3987-93. · 18.37 Impact Factor
• Article: Allogeneic stem cell transplantation for patients with refractory anaemia with matched related and unrelated donors: delay of the transplant is associated with inferior survival.

  Theo de Witte, Ronald Brand, Anja van Biezen, Ghulam Mufti, Tapani Ruutu, Jürgen Finke, Peter von dem Borne, Antonin Vitek, Michel Delforge, Paolo Alessandrino, Nicolas Harlahakis, Nigel Russell, Roberto Martino, Leo Verdonck, Nicholas Kröger, Dietger Niederwieser
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  ABSTRACT: Allogeneic stem cell transplantation (alloSCT) for patients with refractory anaemia may result in a 50% event-free survival, but the high non-relapse mortality (NRM) precludes a general application of this therapeutic modality. This study evaluated the impact of various pre-transplant variables, including disease duration, intensity of the conditioning regimen, type of donor and year of transplantation on outcome. The study population consisted of 374 patients; 244 were transplanted from human leucocyte antigen (HLA)-identical siblings and 130 patients from matched unrelated donors. The median age was 39 years. One hundred and two patients were transplanted after reduced intensity conditioning (RIC). The overall 4-year survival was 52%. The 4-year survival of patients transplanted with HLA-identical sibling donors and matched unrelated donors was 52% and 50%, respectively. Multivariate analysis showed an improved survival (P = 0.05) and a lower NRM (P = 0.02) when the transplantation was performed in recent years. Increasing age, and disease duration of >12 months were associated with inferior survival. RIC resulted in a similar survival despite an increased relapse risk (P = 0.02). This improved outcome permits alloSCT in patients older than 50 years of age, even with the use of matched unrelated donors. AlloSCT should be preferentially performed early after diagnosis after careful analysis of prognostic variables.
  British Journal of Haematology 07/2009; 146(6):627-36. · 4.94 Impact Factor
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  Available from: Argiris Symeonidis

  Article: Risk factors for therapy-related myelodysplastic syndrome and acute myeloid leukemia treated with allogeneic stem cell transplantation.

  Nicolaus Kröger, Ronald Brand, Anja van Biezen, Axel Zander, Judith Dierlamm, Dietger Niederwieser, Agnès Devergie, Tapani Ruutu, Jackie Cornish, Per Ljungman, Alois Gratwohl, Catherine Cordonnier, Dietrich Beelen, Eric Deconinck, Argiris Symeonidis, Theo de Witte
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  ABSTRACT: After successful treatment of malignant diseases, therapy-related myelodysplastic syndrome and acute myeloid leukemia have emerged as significant problems. The aim of this study was to investigate outcome and risk factors in patients with therapy-related myelodysplastic syndrome or acute myeloid leukemia who underwent allogeneic stem cell transplantation. Between 1981 and 2006, 461 patients with therapy-related myelodysplastic syndrome or acute myeloid, a median age of 40 years and a history of solid tumor (n=163), malignant lymphoma (n=133), or other hematologic diseases (n=57) underwent stem cell transplantation and their data were reported to the European Group for Blood and Marrow Transplantation. The cumulative incidence of non-relapse mortality and relapse at 3 years was 37% and 31%, respectively. In a multivariate analysis significant factors for relapse were not being in complete remission at the time of transplantation (p=0.002), abnormal cytogenetics (p=0.005), higher patients' age (p=0.03) and therapy-related myelodysplastic syndrome (p=0.04), while higher non-relapse mortality was influenced by higher patients' age. Furthermore, there was a marked reduction in non-relapse mortality per calendar year during the study period (p<0.001). The 3-year relapse-free and overall survival rates were 33% and 35%, respectively. In a multivariate analysis significant higher overall survival rates were seen per calendar year (p<0.001), for younger age (<40 years) and normal cytogenetics (p=0.05). Using age (<40 years), abnormal cytogenetics and not being in complete remission at the time of transplantation as risk factors, three different risk groups with overall survival rates of 62%, 33% and 24% could be easily distinguished. Allogeneic stem cell transplantation can cure patients with therapy-related myelodysplastic syndrome and acute myeloid leukemia and has markedly improved over time. Non-complete remission, abnormal cytogenetics and higher patients' age are the most significant factors predicting survival.
  Haematologica 04/2009; 94(4):542-9. · 6.42 Impact Factor
• Article: [Allogenic stem cell transplantation in the Netherlands].

  A V M B Schattenberg, Harry C Schouten, Leo F Verdonck, Roel Willemze, J van der Lelie, Peter C Huijgens, Gustaaf W van Imhoff, Anja van Biezen, Ronaldt Brand, A Hagenbeek, Theo de Witte, Jan J Cornelissen
  Nederlands tijdschrift voor geneeskunde 03/2009; 153(9):380-5.
• Article: The role of iron in patients after bone marrow transplantation.

  Theo de Witte
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  ABSTRACT: Haemopoietic stem cell transplantation (HSCT) is an important intervention for malignant and non-malignant blood diseases. However, HSCT is also associated with considerable morbidity and mortality, some of which may be related to iron overload. Levels of serum iron are elevated in patients undergoing HSCT as a result of disturbed iron metabolism, pre-transplantation blood transfusions, or cytotoxic therapy for conditioning before HSCT. The complications of iron overload in HSCT patients include infections, mucositis, chronic liver disease (fibrosis progression), sinusoidal obstruction syndrome, and idiopathic pneumonia syndrome. Iron overload has an adverse impact on survival in patients undergoing HSCT for beta-thalassaemia major or haematological malignancies including myelodysplastic syndromes. It has been suggested that all candidates for and all survivors of HSCT should be screened for iron overload at various time points before and after transplantation. Few studies of iron chelation therapy after HSCT have been reported, but one small study has indicated that deferoxamine is at least as effective as phlebotomy in reducing post-transplantation iron overload in patients with beta-thalassaemia major. The new oral chelator deferasirox may be better tolerated than phlebotomy or deferoxamine infusion, and two prospective phase II studies in patients with iron overload after HSCT are now recruiting candidates.
  Blood reviews 12/2008; 22 Suppl 2:S22-8. · 7.19 Impact Factor
• Article: Allogeneic hematopoietic stem-cell transplantation for chronic lymphocytic leukemia with 17p deletion: a retrospective European Group for Blood and Marrow Transplantation analysis.

  Johannes Schetelig, Anja van Biezen, Ronald Brand, Dolores Caballero, Rodrigo Martino, Maija Itala, José A García-Marco, Liisa Volin, Norbert Schmitz, Rainer Schwerdtfeger, Arnold Ganser, Francesco Onida, Brigitte Mohr, Stephan Stilgenbauer, Martin Bornhäuser, Theo de Witte, Peter Dreger
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  ABSTRACT: Patients with chronic lymphocytic leukemia (CLL) and 17p deletion (17p-) have a poor prognosis. Although allogeneic hematopoietic stem-cell transplantation (HCT) has the potential to cure patients with advanced CLL, it is not known whether this holds true for patients with 17p-CLL. Baseline data from patients, for whom information on the presence of 17p-CLL was available, were downloaded from the European Group for Blood and Marrow Transplantation database. Additional information on the course of CLL and follow-up was collected with a questionnaire. A total of 44 patients with 17p-CLL received allogeneic HCT between March 1995 and July 2006 from a matched sibling (n = 24) or an alternative donor (n = 20). 17p-CLL had been diagnosed by fluorescent in situ hybridization in 82% of patients and by conventional banding in 18% of patients. The median age was 54 years. Before HCT, a median of three lines of chemotherapy had been administered. At HCT, 53% of patients were in remission. Reduced-intensity conditioning was applied in 89% of patients. Acute, grade 2 to 4 graft-versus-host disease (GVHD) occurred in 43% of patients, and extensive chronic GVHD occurred in 53% of patients. At last follow-up, 19 patients were alive, with a median observation time of 39 months (range, 18 to 101 months). Three-year overall survival and progression-free survival rates were 44% and 37%, respectively. The cumulative incidence of progressive disease at 4 years was 34%. No late relapse occurred in nine patients with a follow-up longer than 4 years. Allogeneic HCT has the potential to induce long-term disease-free survival in patients with 17p-CLL.
  Journal of Clinical Oncology 09/2008; 26(31):5094-100. · 18.37 Impact Factor
• Article: Aberrant expression of the hematopoietic-restricted minor histocompatibility antigen LRH-1 on solid tumors results in efficient cytotoxic T cell-mediated lysis.

  Ingrid M Overes, T Henriëtte Levenga, Johanna C M Vos, Agnes van Horssen-Zoetbrood, Robbert van der Voort, Pieter H De Mulder, Theo M de Witte, Harry Dolstra
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  ABSTRACT: CD8(+) T cells recognizing minor histocompatibility antigens (MiHA) on solid tumor cells may mediate effective graft-versus-tumor (GVT) reactivity after allogeneic stem cell transplantation (SCT). Previously, we identified LRH-1 as a hematopoietic-restricted MiHA encoded by the P2X5 gene. Here, we report that LRH-1 is aberrantly expressed on solid tumor cells. P2X5 mRNA expression is demonstrated in a significant portion of solid tumor cell lines, including renal cell carcinoma (RCC), melanoma, colorectal carcinoma, brain cancer and breast cancer. Importantly, P2X5 gene expression was also detected in a subset of primary solid tumor specimens derived from RCC, brain cancer and breast cancer patients. Furthermore, P2X5 expressing solid tumor cells can be effectively targeted by LRH-1-specific cytotoxic T lymphocytes under inflammatory conditions. The expression of HLA-B7 and CD54 on tumor cells increases upon cytokine stimulation resulting in improved T cell activation as observed by higher levels of degranulation and enhanced tumor cell lysis. Overall, hematopoietic-restricted MiHA LRH-1 is aberrantly expressed on solid tumor cells and may be used as target in GVT-specific immunotherapy after SCT.
  Cancer Immunology and Immunotherapy 09/2008; 58(3):429-39. · 3.70 Impact Factor