Publications (13)95.57 Total impact
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Article: Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial.
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ABSTRACT: We investigated whether bortezomib during induction and maintenance improves survival in newly diagnosed multiple myeloma (MM). In all, 827 eligible patients with newly diagnosed symptomatic MM were randomly assigned to receive induction therapy with vincristine, doxorubicin, and dexamethasone (VAD) or bortezomib, doxorubicin, and dexamethasone (PAD) followed by high-dose melphalan and autologous stem-cell transplantation. Maintenance consisted of thalidomide 50 mg (VAD) once per day or bortezomib 1.3 mg/m(2) (PAD) once every 2 weeks for 2 years. The primary analysis was progression-free survival (PFS) adjusted for International Staging System (ISS) stage. Complete response (CR), including near CR, was superior after PAD induction (15% v 31%; P < .001) and bortezomib maintenance (34% v 49%; P < .001). After a median follow-up of 41 months, PFS was superior in the PAD arm (median of 28 months v 35 months; hazard ratio [HR], 0.75; 95% CI, 0.62 to 0.90; P = .002). In multivariate analysis, overall survival (OS) was better in the PAD arm (HR, 0.77; 95% CI, 0.60 to 1.00; P = .049). In high-risk patients presenting with increased creatinine more than 2 mg/dL, bortezomib significantly improved PFS from a median of 13 months to 30 months (HR, 0.45; 95% CI, 0.26 to 0.78; P = .004) and OS from a median of 21 months to 54 months (HR, 0.33; 95% CI, 0.16 to 0.65; P < .001). A benefit was also observed in patients with deletion 17p13 (median PFS, 12 v 22 months; HR, 0.47; 95% CI, 0.26 to 0.86; P = .01; median OS, 24 months v not reached at 54 months; HR, 0.36; 95% CI, 0.18 to 0.74; P = .003). Bortezomib during induction and maintenance improves CR and achieves superior PFS and OS.Journal of Clinical Oncology 07/2012; 30(24):2946-55. · 18.37 Impact Factor -
Article: Donor versus no-donor comparison of newly diagnosed myeloma patients included in the HOVON-50 multiple myeloma study.
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ABSTRACT: To prospectively evaluate allogeneic stem cell transplantation (allo-SCT) for myeloma as part of first-line therapy, a donor versus no-donor analysis was performed of patients treated in the HOVON-50 study, a study that was originally designed to examine thalidomide combined with intensive therapy. Two hundred sixty patients having received an autologous-SCT fulfilled the criteria to be included, 138 patients without an HLA-identical sibling donor and 122 patients with a donor. After a median follow-up of 77 months, complete remission, progression-free survival (PFS), and overall survival were not significantly different between the 2 groups. PFS at 6 years was 28% for patients with a donor versus 22% for patients without a donor (P = .19) and overall survival at 6 years from high-dose melphalan was 55%, irrespective of having a donor (P = .68). Cumulative incidence of nonrelapse mortality at 6 years after autologous-SCT was 16% in the donor group versus 3% in the no-donor group (P < .001). However, PFS was significantly prolonged in the 99 patients who actually proceeded to allo-SCT compared with the 115 patients who continued maintenance or received a second high-dose melphalan, but the difference did not translate into a prolonged survival benefit. These results do not support a general application of allo-SCT in all myeloma patients as part of first-line therapy.Blood 03/2012; 119(26):6219-25; quiz 6399. · 9.90 Impact Factor -
Article: Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab.
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ABSTRACT: In our efforts to develop novel effective treatment regimens for multiple myeloma we evaluated the potential benefits of combining the immunomodulatory drug lenalidomide with daratumumab. Daratumumab is a novel human CD38 monoclonal antibody which kills CD38+ multiple myeloma cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and apoptosis. To explore the effect of lenalidomide combined with daratumumab, we first carried out standard antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity assays in which the CD38+ multiple myeloma cell line UM-9 and primary multiple myeloma cells isolated from patients were used as target cells. We also tested the effect of lenalidomide on daratumumab-dependent cell-mediated-cytotoxicity and complement-dependent cytotoxicity of multiple myeloma cells directly in the bone marrow mononuclear cells of multiple myeloma patients. Finally, we determined the daratumumab-dependent cell-mediated cytotoxicity using peripheral blood mononuclear cells of multiple myeloma patients receiving lenalidomide treatment. Daratumumab-dependent cell-mediated cytotoxicity of purified primary multiple myeloma cells, as well as of the UM-9 cell line, was significantly augmented by lenalidomide pre-treatment of the effector cells derived from peripheral blood mononuclear cells from healthy individuals. More importantly, we demonstrated a clear synergy between lenalidomide and daratumumab-induced antibody-dependent cell-mediated cytotoxicity directly in the bone marrow mononuclear cells of multiple myeloma patients, indicating that lenalidomide can also potentiate the daratumumab-dependent lysis of myeloma cells by activating the autologous effector cells within the natural environment of malignant cells. Finally, daratumumab-dependent cell-mediated cytotoxicity was significantly up-regulated in peripheral blood mononuclear cells derived from 3 multiple myeloma patients during lenalidomide treatment. Our results indicate that powerful and complementary effects may be achieved by combining lenalidomide and daratumumab in the clinical management of multiple myeloma.Haematologica 02/2011; 96(2):284-90. · 6.42 Impact Factor -
Article: Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: the HOVON 49 Study.
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ABSTRACT: For several decades, the treatment of elderly patients with multiple myeloma (MM) has consisted of melphalan and prednisone (MP). The Dutch-Belgium Hemato-Oncology Cooperative Group (HOVON) investigated the efficacy of thalidomide added to MP (MP-T) in a randomized phase III trial. The objective of this study was to investigate the efficacy, toxicity, and effects on quality of life of MP-T. A randomized phase III trial compared standard MP with MP-T (thalidomide 200 mg/d) in newly diagnosed patients with multiple myeloma older than age 65 years. Maintenance therapy with thalidomide 50 mg/d was administered to patients after MP-T until relapse. The primary end point was event-free survival (EFS); response rate, overall survival (OS), and progression-free survival (PFS) were secondary end points. An intent-to-treat analysis of 333 evaluable patients showed significantly higher response rates in MP-T-treated patients compared with MP-treated patients a response (> or = partial response: 66% v 45%, respectively; P < .001; and > or = very good partial response [VGPR]: 27% v 10%, respectively; P < .001). EFS was 13 months with MP-T versus 9 months with MP (P < .001). OS was 40 months with MP-T versus 31 months with MP (P = .05). This study demonstrates that thalidomide improves the response rate and VGPR in elderly patients with newly diagnosed MM. MP-T also results in a better EFS, PFS, and OS.Journal of Clinical Oncology 07/2010; 28(19):3160-6. · 18.37 Impact Factor -
Article: Analysis of efficacy and prognostic factors of lenalidomide treatment as part of a Dutch compassionate use program.
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ABSTRACT: 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. 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 < .0001). Lenalidomide toxicity was predominantly hematologic (37%; Common Toxicity Criteria > or = 3) and the incidence of venous thrombotic events was low (5%) using the recommended prophylaxis. This analysis confirms that, outside clinical prospective trials, treatment with lenalidomide is highly effective and feasible in heavily pretreated patients with multiple myeloma.Clinical lymphoma, myeloma & leukemia 04/2010; 10(2):138-43. -
Article: On the added value of baseline FDG-PET in malignant lymphoma.
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ABSTRACT: The added value of baseline positron emission tomography (PET) scans in therapy evaluation in malignant lymphoma is unclear. In guidelines, baseline PET is recommended but not mandatory except in lymphoma types with variable fluoro-D-glucose uptake. The aim of the present study was to test the hypothesis that adding baseline PET information decreases false positive readings with posttreatment PET and improves observer agreement. Forty-four patients (mean age 56 years, standard deviation 14) with malignant lymphoma were included. Two nuclear medicine physicians retrospectively and independently evaluated the posttreatment PET, 3 weeks later followed by paired reading of baseline and posttreatment PET. For each PET, 22 regions were classified as positive, negative, or equivocal, resulting in an overall PET score of positive, unclear, or negative. In case of discrepancies, consensus was reached. Addition of baseline to posttreatment PET evaluation affected the classification of metabolic response in 34% of malignant lymphoma patients treated with first-line chemotherapy. In one out of seven patients, addition of the baseline PET lead to opposite conclusions (95% confidence interval 4-14). False positivity was reduced by adding the baseline scan information, but the effect on false negativity was similar. In addition, the amount of unclear classifications halved after paired reading. Observer agreement did not improve upon adding the baseline PET data. Without any other clinical information, pretreatment PET facilitates changes the interpretation of a posttreatment PET in a third of the patients, resulting in both upgrading and downgrading of the posttreatment situation of a malignant lymphoma patient. If these results are confirmed for PET-computed tomography systems, they favor the addition of baseline PET to the current work-up of patients with malignant lymphoma.Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 10/2009; 12(2):225-32. · 2.47 Impact Factor -
Article: A dutch family with Hb Debrousse: severe anemia after parvovirus B19 infection.
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ABSTRACT: Hb Debrousse [beta96(FG3)Leu-->Pro] is an unstable hemoglobin (Hb) variant with high oxygen affinity. We describe a case of chronic compensated hemolysis in a 39-year-old woman in whom the variant was found. Soon after the diagnosis was made, she and her son were admitted to the hospital with severe anemia due to Parvovirus B19 infection. The son also appeared to have the Hb Debrousse variant. Parvovirus B19 infection is a life-threatening disease in patients with (compensated) hemolysis.Hemoglobin 01/2009; 33(3):269-73. · 1.30 Impact Factor -
Article: In vivo dynamics of stable chronic lymphocytic leukemia inversely correlate with somatic hypermutation levels and suggest no major leukemic turnover in bone marrow.
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ABSTRACT: Although accumulating evidence indicates that chronic lymphocytic leukemia (CLL) is a disease with appreciable cell dynamics, it remains uncertain whether this also applies to patients with stable disease. In this study, (2)H(2)O was administered to a clinically homogeneous cohort of nine stable, untreated CLL patients. CLL dynamics in blood and bone marrow were determined and compared with normal B-cell dynamics in blood from five healthy individuals who underwent a similar (2)H(2)O labeling protocol. Average CLL turnover rates (0.08-0.35% of the clone per day) were approximately 2-fold lower than average B-cell turnover rates from healthy individuals (0.34-0.89%), whereas the rate at which labeled CLL cells in blood disappeared (0.00-0.39% of B cells per day) was approximately 10-fold lower compared with labeled B cells from healthy individuals (1.57-4.24% per day). Leukemic cell turnover variables inversely correlated with the level of somatic hypermutation of the CLL clone (IgVH mutations). Although CLL cells in bone marrow had a higher level of label enrichment than CLL cells in blood, no difference between proliferation rates and proapoptotic and antiapoptotic profiles of CLL cells from these compartments was observed. These data suggest that, in stable disease, there is a biological relationship between the degree of somatic hypermutation of the CLL clone and its dynamics in vivo. Furthermore, in contrast to lymph nodes, the bone marrow does not seem to be a major CLL proliferation site.Cancer Research 01/2009; 68(24):10137-44. · 7.86 Impact Factor -
Article: Thalidomide in induction treatment increases the very good partial response rate before and after high-dose therapy in previously untreated multiple myeloma.
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ABSTRACT: In the prospective phase 3 HOVON-50/GMMG-HD3 trial, patients randomized to TAD (thalidomide, doxorubicin, dexamethasone) had a significantly higher response rate (at least PR) after induction compared with patients randomized to VAD (vincristine, adriamycin, dexamethasone, 72% vs. 54%, p<0.001). Complete remission (CR) and very good partial remission (VGPR) were also higher after TAD. After High Dose melphalan 200mg/m(2) response was comparable in both arms, 76% and 79% respectively. However, CR plus VGPR were significantly higher in the patients randomized to TAD (49% vs. 32%, p<0.001). CTC grade 3-4 adverse events were similar in both arms.Haematologica 01/2008; 93(1):124-7. · 6.42 Impact Factor -
Article: Pericardial involvement in a non-Hodgkin lymphoma patient: coregistered FDG-PET and CT imaging.
European Heart Journal 12/2007; 28(22):2698. · 10.48 Impact Factor -
Article: High levels of serum prostate-specific antigen due to PSA producing follicular non-Hodgkin's lymphoma.
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ABSTRACT: Both carcinoma of the prostate and non-Hodgkin's lymphoma are common in elderly patients. Measurement of serum prostate-specific antigen (PSA) is a frequently used tool to diagnose and monitor prostate carcinoma and is generally specific for diseases of the prostate. We describe a 68-yr-old patient with voiding difficulties and high PSA levels, but without inflammatory or malignant changes upon multiple transrectal ultrasound guided prostate biopsies. Digital rectal examination was normal. Laboratory showed a strongly elevated PSA level (62 microg/L, Immulight 2000); DPC, USA). A CT-scan showed a retroperitoneal process with mass in the right pelvis and infiltration of the bladder wall, suggestive for metastatic prostate carcinoma. Surgical excision of an axillary lymph node set the diagnosis at a stage IV follicular lymphoma, Berard grade I to II in which the majority of neoplastic cells expressed PSA. After lymphoma-specific treatment, there was a positron emission tomography (PET) confirmed complete remission with normal PSA levels (6 microg/L), which still persists. Although rare, high PSA levels can be due to the presence of non-Hodgkin's lymphoma. Such a diagnosis should be considered when patients present with lymphadenopathy other than regional prostatic lymphadenopathy.European Journal Of Haematology 09/2007; 79(2):155-8. · 2.61 Impact Factor -
Article: Dose-finding study of high-dose simvastatin combined with standard chemotherapy in patients with relapsed or refractory myeloma or lymphoma.
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ABSTRACT: In vitro statins induce apoptosis in myeloma and lymphoma cells in a dose-and time-dependent way. In combination with dexamethasone and doxorubicin, statins have a chemo-sensitizing effect. Twenty-eight patients with relapsed myeloma or lymphoma were treated with a dose-escalating regimen of simvastatin for 7 days followed by VAD in myeloma patients and CHOP in lymphoma patients. The maximum tolerated dose was 15 mg/kg/day simvastatin. The most frequently reported side-effects were fatigue, gastrointestinal CTC grade 1-2 and neutropenic fever. The dose-limiting toxicity was neutropenic sepsis and grade 3 gastrointestinal side effects. High-dose simvastatin given immediately prior to chemotherapy is safe and tolerable up to a dose of 15 mg/kg/day.Haematologica 05/2006; 91(4):542-5. · 6.42 Impact Factor -
Article: Factor VIII inhibitor in a patient with mild haemophilia A and an Asn618-->Ser mutation responsive to immune tolerance induction and cyclophosphamide.
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ABSTRACT: We describe a patient with mild haemophilia A (original value of factor VIII activity 0.30 U/ml) who developed an inhibitor (36.1 Bethesda U/ml) which cross-reacted with his endogenous factor VIII. This caused a decline in basal factor VIII level (< 0.01 U/ml) and severe haemorrhagic events. Treatment to induce immune tolerance was started with factor VIII/von Willebrand factor (VWF) concentrates, but inhibitor levels increased progressively and the patient suffered serious bleeding. Cyclophosphamide was administered and, after 8 months treatment, factor VIII levels increased to 0.20 U/ml and the inhibitor could no longer be detected. Screening of his factor VIII gene revealed a missense mutation in exon 13 that predicts substitution of Asn618-->Ser in the A2 domain of factor VIII. Immunoprecipitation analysis showed that the antibodies present in the patient's plasma reacted with metabolically labelled A2 domain and, to a lesser extent, with factor VIII light chain. Inhibitory antibodies were completely neutralized by recombinant A2 domain, whereas no neutralization was observed after the addition of factor VIII light chain (A3-C1-C2) and C2 domain. More detailed analysis showed that the majority of inhibitory antibodies were directed against residues Arg484-Ile508, a previously identified binding site for factor VIII inhibitors. Our findings suggest that immune tolerance therapy and cyclophosphamide were successful in eradicating inhibitory antibodies against a common epitope on factor VIII.British Journal of Haematology 04/2002; 117(1):136-40. · 4.94 Impact Factor
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2007
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Universitair Medisch Centrum Utrecht
Utrecht, Provincie Utrecht, Netherlands
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