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Vitamin C is an important micronutrient for various immune cells. It increases phagocytic cell function and is necessary for T and natural killer (NK) cell development. Patients in need of an autologous hematopoietic stem cell... more
Vitamin C is an important micronutrient for various immune cells. It increases phagocytic cell function and is necessary for T and natural killer (NK) cell development. Patients in need of an autologous hematopoietic stem cell transplantation (HSCT) are often vitamin C-depleted. We therefore hypothesized that vitamin C supplementation could improve immune recovery in autologous HSCT patients. This blinded, placebo-controlled trial included 44 patients randomized to receive vitamin C or a placebo. The following outcome measures used were clinical and immunological parameters, among others: time to neutrophil recovery, serum, and intracellular vitamin C values. Twenty-one patients received vitamin C, and 23 received a placebo. The time to neutrophil recovery did not differ between the two groups at 11.2 days (p = 0.96). There were no differences in hospitalization time (19.7 vs. 19.1 days, p = 0.80), the incidence of neutropenic fever (57% vs. 78%, p = 0.20), or 3-month overall surviv...
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Infusion of ex vivo expanded and cytokine-activated natural killer (NK) cells is a promising alternative way to treat multiple myeloma (MM). However, the tumor microenvironment (TME) may suppress their function. While reduced glucose... more
Infusion of ex vivo expanded and cytokine-activated natural killer (NK) cells is a promising alternative way to treat multiple myeloma (MM). However, the tumor microenvironment (TME) may suppress their function. While reduced glucose availability is a TME hallmark of many solid tumors, glucose levels within the TME of hematological malignancies residing in the bone marrow (BM) remain unknown. Here, we measured glucose levels in the BM of MM patients and tested the effect of different glucose levels on NK cells. BM glucose levels were measured using a biochemical analyzer. Compared to the normal range of blood glucose, BM glucose levels were lower in 6 of 9 patients (479-1231 mg/L; mean=731.8 mg/L). The effect of different glucose levels on NK cell cytotoxicity was tested in 4-hour cytotoxicity assays with tumor cells. 500 mg/L glucose (representing low range of MM BM) during the 4-hour cytotoxicity assay did not negatively affect cytotoxicity of activated NK cells, while higher gluc...
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Research Interests: Chemistry, Immunology, Hypoxia, Cytotoxicity, Medicine, and 12 moreAntibodies, Tumor microenvironment, Therapy, Multiple Myeloma, ADCC, Inhibition, Expression, CD, Nk, NK cells, Pathway, and degranulation(Antibodies, Tumor microenvironment, Therapy, Multiple Myeloma, ADCC, Inhibition, Expression, CD, Nk, NK cells, Pathway, and degranulation)
(Antibodies, Tumor microenvironment, Therapy, Multiple Myeloma, ADCC, Inhibition, Expression, CD, Nk, NK cells, Pathway, and degranulation)
Background: We recently reported the results of the phase III randomized HOVON87/NMSG18 study showing comparable efficacy of treatment with melphalan, prednisolone and thalidomide following by thalidomide maintenance (MPT-T) versus... more
Background: We recently reported the results of the phase III randomized HOVON87/NMSG18 study showing comparable efficacy of treatment with melphalan, prednisolone and thalidomide following by thalidomide maintenance (MPT-T) versus melphalan, prednisolone and lenalidomide followed by lenalidomide maintenance (MPR-R) (Zweegman S et al. Blood 2016;127(9):1109- 1116). As not only efficacy but also potential toxicity affecting quality of life (QoL) guides the choice of treatment, health-related (HR) QoL is important. Aims: To evaluate the HRQoL results of the HOVON87/NMSG18 study. Methods: Two validated HRQoL instruments (EORTC QLQ-C30 and MY20) were obtained at baseline, after 3 and 9 induction cycles (3ID and 9ID) and after 6 and 12 months of maintenance therapy (6MT and 12MT). The subscales global QoL, physical functioning, pain, fatigue, constipation, diarrhea, nausea/vomiting, insomnia, disease symptoms, side effects of treatment and neuropathy were analysed. Change in HRQoL score ...
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Randomized Phase III Trial in Non-Transplant Eligible Patients with Newly Diagnosed Symptomatic Multiple Myeloma Comparing Melphalan-Prednisone-Thalidomide Followed By Thalidomide Maintenance (MPT-T) Versus Melphalan-Prednisone-Lenalidomide Followed By Maintenance with Lenalidomide (MPR-R); A Joi...more
Background Melphalan-based regimens, combined with Prednisone and Thalidomide (THAL)(MPT) or Bortezomib (V)(MPV), have been approved as standard therapy of non-transplant eligible newly diagnosed multiple myeloma (NDMM) patients. Similar... more
Background Melphalan-based regimens, combined with Prednisone and Thalidomide (THAL)(MPT) or Bortezomib (V)(MPV), have been approved as standard therapy of non-transplant eligible newly diagnosed multiple myeloma (NDMM) patients. Similar to MPT and MPV also MP-Lenalidomide followed by Lenalidomide (LEN) maintenance (MPR-R) has a superior PFS compared to MP. We compared MPT followed by THAL maintenance (MPT-T) versus MPR-R in non-transplant eligible NDMM patients. Study design Patients were randomised to receive nine 4-weekly cycles of MPT (MEL 0.18 mg/kg days 1-4, PRED 2 mg/kg days 1-4 plus THAL 200 mg days1-28) followed by THAL maintenance 100 mg d1-28 until progression or nine cycles of MPR (MEL 0.18 mg/kg days 1-4, PRED 2 mg/kg days 1-4 plus LEN 10 mg days 1-21) followed by LEN maintenance 10 mg d1-21 until progression. In order to detect an improvement of progression free survival (PFS) with 90% power and a HR of 0.714 for patients receiving MPR-R, 668 patients had to be randomi...
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Introduction We previously reported the results of the phase III randomized HOVON-87/NMSG-18 study for Newly Diagnosed Multiple Myeloma patients not eligible for stem cell transplantation (nte-NDMM). The efficacy of melphalan,... more
Introduction We previously reported the results of the phase III randomized HOVON-87/NMSG-18 study for Newly Diagnosed Multiple Myeloma patients not eligible for stem cell transplantation (nte-NDMM). The efficacy of melphalan, prednisolone and either thalidomide followed by thalidomide maintenance (MPT-T) versus lenalidomide followed by lenalidomide maintenance (MPR-R) was found to be comparable, being consistent across subgroups defined by age, cytogenetic risk and ISS [1]. As frailty is known to affect clinical outcome, we investigated the impact of frailty on outcome. Methods Frailty was assessed by a modification of the IMWG frailty score based on age, the Charlson Comorbidity Index (retrospectively retrieved from the list of comorbidities that were present at entry) and the WHO performance as a proxy for (instrumental) Activities of Daily Living ((i)ADL). To assess the effect of frailty on progression free survival (PFS) and OS, the logrank test was used, while the chi-squared ...
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Natural killer (NK) cells mediate potent anti-tumor responses, which makes them attractive targets for immunotherapy. The anti-tumor response of endogenous- or allogeneic NK cells can be enhanced through clinically available monoclonal... more
Natural killer (NK) cells mediate potent anti-tumor responses, which makes them attractive targets for immunotherapy. The anti-tumor response of endogenous- or allogeneic NK cells can be enhanced through clinically available monoclonal antibodies that mediate antibody-dependent cellular cytotoxicity (ADCC). NK cell activation is regulated by interaction of inhibitory receptors with classical- and non-classical human leukocyte antigens (HLA) class I molecules. Inhibitory receptors of the killer immunoglobulin-like receptor (KIR) family interact with HLA-A, -B or –C epitopes, while NKG2A interacts with the non-classical HLA-E molecule. Both types of inhibitory interactions may influence the strength of the ADCC response. In the present review, we provide an overview of the effect of inhibitory KIRs and NKG2A on NK cell-mediated ADCC, which highlights the rationale for combination strategies with ADCC triggering antibodies and interference with the NK cell relevant inhibitory immune ch...
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Flow cytometric analysis of NK cell purity. NK cells were gated in the FSC/SSC on the lymphocyte gate and dead cells were excluded by live/dead staining (7-AAD). Percentages of CD19+, CD3+, CD56+CD3−, CD56−CD16+ are indicated in the... more
Flow cytometric analysis of NK cell purity. NK cells were gated in the FSC/SSC on the lymphocyte gate and dead cells were excluded by live/dead staining (7-AAD). Percentages of CD19+, CD3+, CD56+CD3−, CD56−CD16+ are indicated in the plots. (TIFF 274 kb)
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Interview guide. (DOCX 18 kb)
Supplementation of rhIFN-γ during poly(I:C)-DC maturation and its effect on cytokine and chemokine secretion. iDC were matured in serum-free medium supplemented with poly(I:C), IL-4, and GM-CSF in the presence of increasing concentrations... more
Supplementation of rhIFN-γ during poly(I:C)-DC maturation and its effect on cytokine and chemokine secretion. iDC were matured in serum-free medium supplemented with poly(I:C), IL-4, and GM-CSF in the presence of increasing concentrations of rhIFN-γ. Cytokine and chemokine profiles were determined in the culture supernatants after 48 h of maturation by CBA. Three individual donors are shown. (TIFF 1638 kb)
EBMT Meeting 2016 Effect of graft source on safety and efficacy in patients undergoing hematopoietic stem cell transplantation Stephan Mielke* 1, Johan Maertens2, Dominik Selleslag3, Phillippe Lewalle4, Irwin Walker5, DenisClaude Roy6,... more
EBMT Meeting 2016 Effect of graft source on safety and efficacy in patients undergoing hematopoietic stem cell transplantation Stephan Mielke* 1, Johan Maertens2, Dominik Selleslag3, Phillippe Lewalle4, Irwin Walker5, DenisClaude Roy6, Gerard Bos7, Steven Devine8, Dragana Milojkovic9, Lisya Gerez10, Kees Meewisse10, Karen Reitsma10, Manfred Rüdiger10, Jeroen Rovers10 1 Division of Hematology and Oncology, Department of Medicine II, Julius-Maximilian-University, Würzburg, Germany, 2 Department of Haematology, University Hospital Gasthuisberg, Leuven, 3 Department of Hematology, AZ Sint-Jan Brugge-Oostende AV, Brugge, 4 Laboratory of Experimental Hematology, Institut Jules Bordet, ULB, Brussels, Belgium, 5 Department of Medicine, Juravinski Hospital and Cancer Centre, Hamilton, 6 Blood and Marrow Transplantation Program, Div. of Hematology-Oncology, Hôpital Maisonneuve-Rosemont, University of Montreal, Quebec, Canada, 7 Department of Hematology, University Hospital Maastricht, Maastri...
PURPOSE To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial. PATIENTS AND METHODS The EMN02/HOVON95 trial compared consolidation treatment... more
PURPOSE To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial. PATIENTS AND METHODS The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS). RESULTS Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenet...
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In this article we explore the ethical issues raised by permitting patients to pay for participation (P4) in clinical trials, and discuss whether there are any categorical objections to this practice. We address key considerations... more
In this article we explore the ethical issues raised by permitting patients to pay for participation (P4) in clinical trials, and discuss whether there are any categorical objections to this practice. We address key considerations concerning payment for participation in trials, including patient autonomy, risk/benefit and justice, taking account of two previous critiques of the ethics of P4. We conclude that such trials could be ethical under certain strict conditions, but only if other potential sources of funding have first been explored or are unavailable.
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Subgroups. (DOCX 20 kb)
Additional demographics. (DOCX 20 kb)
Cytokine-activated NK cells mediate their help for DC maturation via IFN-γ. NK cells were activated for 16 h in the presence of IL-18 (100 ng/ml) and IL-2 (1000 U/ml). Cell-free supernatants were harvested after overnight incubation and... more
Cytokine-activated NK cells mediate their help for DC maturation via IFN-γ. NK cells were activated for 16 h in the presence of IL-18 (100 ng/ml) and IL-2 (1000 U/ml). Cell-free supernatants were harvested after overnight incubation and added to iDC supplemented with IL-4 and GM-CSF. Blocking antibodies were added where indicated (x-axis). The negative control (− ctrl) represents iDC which have been matured in the presence of IL-2 and IL-18 without NK cell-derived soluble factors. Data are shown as mean of 11 independent experiments. Mann-Whitney U test comparing differences between untreated DC and blocking conditions. ** P ≤ 0.01. (TIFF 1481 kb)
Given the growing interest in ascorbic acid (AA), there is a need for a reliable and reproducible method to measure AA status in the human body. Serum AA concentrations do not correlate well with tissue levels, but AA levels in leukocytes... more
Given the growing interest in ascorbic acid (AA), there is a need for a reliable and reproducible method to measure AA status in the human body. Serum AA concentrations do not correlate well with tissue levels, but AA levels in leukocytes do. However, a standard method for clinical application is lacking. This present study describes a method to measure AA in the peripheral blood mononuclear cells (PBMCs) with hydrophilic interaction liquid chromatography (HILIC). The method can also be used in plasma and other leukocyte subsets. The measurements of AA in PBMCs and plasma were performed with HPLC with HILIC separation and UV detection. The sample preparation involved the isolation of PBMCs and lysis and precipitation with acetonitrile. European Medicine Agency guidelines for bioanalytic method validation were followed for the evaluation. A highly precise execution of the method was found with intra- and inter-assay variations at a maximum of 7.8%. In 40 healthy donors, a mean intrac...
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Antibodies are commonly used in cancer immunotherapy because of their high specificity for tumor-associated antigens. The binding of antibodies can have direct effects on tumor cells but also engages natural killer (NK) cells via their Fc... more
Antibodies are commonly used in cancer immunotherapy because of their high specificity for tumor-associated antigens. The binding of antibodies can have direct effects on tumor cells but also engages natural killer (NK) cells via their Fc receptor. Mucin 1 (MUC1) is a highly glycosylated protein expressed in normal epithelial cells, while the under-glycosylated MUC1 epitope (MUC1-Tn/STn) is only expressed on malignant cells, making it an interesting diagnostic and therapeutic target. Several anti-MUC1 antibodies have been tested for therapeutic applications in solid tumors thus far without clinical success. Herein, we describe the generation of fully humanized antibodies based on the murine 5E5 antibody, targeting the tumor-specific MUC1-Tn/STn epitope. We confirmed that these antibodies specifically recognize tumor-associated MUC1 epitopes and can activate human NK cells in vitro. Defucosylation of these newly developed anti-MUC1 antibodies further enhanced antigen-dependent cellul...
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BACKGROUND Allogeneic hematopoietic stem cell transplantation (HSCT) is increasingly used, but this treatment is complex and costly. As clinical outcomes of HSCT with matched unrelated donor (MUD) and haploidentical donors are similar,... more
BACKGROUND Allogeneic hematopoietic stem cell transplantation (HSCT) is increasingly used, but this treatment is complex and costly. As clinical outcomes of HSCT with matched unrelated donor (MUD) and haploidentical donors are similar, costs could influence donor choice. METHOD We retrospectively compared resource utilization and costs of HSCT using the three different donor types (matched related donor (MRD) (n=32), haploidentical related (n=30) and MUD (n=60)) within the first year after transplantation. Costs were analysed through a bottom up method. Non-parametric bootstrapping was applied to test for statistical differences in costs. Subgroup analyses were performed to identify predictors for costs. RESULTS Cost pre-transplant for search and acquisition of the graft were significantly higher in MUD HSCT (€35,222) versus MRD and haploidentical HSCT (€15,356 and €16,097, respectively). The costs of haploidentical HSCT were the highest in the transplant phase. Main cost factors were inpatient days and medication. Overall, the costs for haploidentical and MUD HSCT were similar (€115,724 for MUD, €113,312 for haploidentical). CONCLUSION Our study suggests no difference in total transplantation costs between allogeneic HSCT using a MUD or a haploidentical donor. Since clinical outcomes seem similar as well, the choice of donor type might be based on availability, speed, and logistics.
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Disease relapse is an important problem after allogeneic stem cell transplantations in multiple myeloma (MM). To test the hypothesis that natural killer (NK) cell alloreactivity in the setting of a haploidentical stem cell transplantation... more
Disease relapse is an important problem after allogeneic stem cell transplantations in multiple myeloma (MM). To test the hypothesis that natural killer (NK) cell alloreactivity in the setting of a haploidentical stem cell transplantation (haploSCT) can reduce the risk of myeloma relapse, we performed a small prospective phase 2 study in which we transplanted poor-risk MM patients using a killer cell immunoglobulin-like receptor (KIR)-ligand mismatched haploidentical donor. Patients received bone marrow grafts after reduced-intensity conditioning, with post-transplantation cyclophosphamide (PTCY) graft-versus-host-disease (GVHD) prophylaxis. The primary endpoint was 1.5-year progression-free survival (PFS); stopping rules were installed in case interim results made a benefit of 50% PFS at 1.5 years unlikely. After inclusion of 12 patients, of which 9 were evaluable for the primary endpoint, all patients relapsed within a median time of 90 days. All except 1 patient showed engraftmen...
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Introduction ATIR101 is a donor-derived, T-cell-enriched leukocyte preparation depleted ex vivo of host-alloreactive T cells. When administered as a single, adjunctive infusion after T-cell-depleted haploidentical hematopoietic stem cell... more
Introduction ATIR101 is a donor-derived, T-cell-enriched leukocyte preparation depleted ex vivo of host-alloreactive T cells. When administered as a single, adjunctive infusion after T-cell-depleted haploidentical hematopoietic stem cell transplantation (haplo HSCT), ATIR101 may reduce serious complications resulting from delayed immune reconstitution such as infections and relapse. In a Phase II study, patients with hematologic malignancies who received ATIR101 had an overall survival (OS) of 61% and no Grade III/IV acute graft-versus-host disease (GVHD) at 1 year post HSCT (Roy DC et al. ASH 2016). Similarly, an OS rate of 55% was reported in a second Phase II study (Olavarria E et al. EHA 2018). We report multivariable and subgroup analyses of a pooled dataset from these two Phase II studies of ATIR101, compared with a dataset of control patients meeting similar inclusion/exclusion criteria who underwent T-cell-depleted haplo HSCT without ATIR101, to assess the impact of potentia...
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Introduction: Daratumumab (DARA) monotherapy is effective and well tolerated in heavily pretreated relapsed/refractory multiple myeloma (RRMM) patients. However, approximately 70% of patients do not respond and eventually all patients... more
Introduction: Daratumumab (DARA) monotherapy is effective and well tolerated in heavily pretreated relapsed/refractory multiple myeloma (RRMM) patients. However, approximately 70% of patients do not respond and eventually all patients will develop progressive disease. DARA treatment results in depletion of CD38+ immune suppressor cells and thereby increased T cell frequencies. A partner drug with immune stimulating activity through a different mechanism of action could further improve the efficacy of DARA. As a single agent, the Programmed Death (PD)-1 checkpoint inhibitor nivolumab induced only stable disease in 67% of RRMM. Immune modulation through targeting CD38 combined with blocking the PD-1/PD-L1 axis may lead to improved T and NK cell activity and therefore better anti-MM efficacy. Preclinical studies showed that cyclophosphamide has synergistic activity with both DARA and PD-1 inhibitors. In this study, we investigate the efficacy and safety of DARA combined with nivolumab,...
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Older acute myeloid leukemia (AML) patients have a poor prognosis, therefore novel therapies are needed. Allogeneic natural killer (NK) cells have been adoptively transferred with promising clinical results. Here, we report the... more
Older acute myeloid leukemia (AML) patients have a poor prognosis, therefore novel therapies are needed. Allogeneic natural killer (NK) cells have been adoptively transferred with promising clinical results. Here, we report the first-in-human study exploiting an unique scalable NK cell product generated ex vivo from CD34+ hematopoietic stem and progenitor cells (HSPCs) from partially HLA-matched umbilical cord blood units. Ten older AML patients in morphologic complete remission received an escalating HSPC-NK cell dose (between 3 and 30x10^6/kg body weight) after lymphodepleting chemotherapy without cytokine boosting. HSPC-NK cell products contained a median of 75% highly activated NK cells, with <1x10^4 T cells/kg and <3x10^5 B cells/kg body weight. HSPC-NK cells were well tolerated and no graft-versus-host disease nor toxicity was observed. Despite no cytokine boosting was given, transient HSPC-NK cell persistence was clearly found in peripheral blood up to 21% until day 8, ...
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The prognosis of multiple myeloma (MM) patients who become refractory to lenalidomide and bortezomib is very poor, indicating the need for new therapeutic strategies for these patients. Next to the development of new drugs, the strategy... more
The prognosis of multiple myeloma (MM) patients who become refractory to lenalidomide and bortezomib is very poor, indicating the need for new therapeutic strategies for these patients. Next to the development of new drugs, the strategy of combining agents with synergistic activity may also result in clinical benefit for patients with advanced myeloma. We have previously shown in a retrospective analysis that lenalidomide combined with continuous low-dose cyclophosphamide and prednisone (REP) had remarkable activity in heavily pretreated, lenalidomide-refractory MM patients. To evaluate this combination prospectively, we initiated a phase 1/2 study to determine the optimal dose and to assess its efficacy and safety in lenalidomide-refractory MM patients. The maximum tolerated dose (MTD) was defined as 25 mg lenalidomide (days 1-21/28 days), combined with continuous cyclophosphamide (50 mg/day) and prednisone (20 mg/day). At the MTD (n=67 patients), the overall response rate was 67%,...
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Accumulating evidence indicates that fractionated radiotherapy (RT) can result in distant non-irradiated (abscopal) tumour regression. Although preclinical studies indicate the importance of T cells in this infrequent phenomenon, these... more
Accumulating evidence indicates that fractionated radiotherapy (RT) can result in distant non-irradiated (abscopal) tumour regression. Although preclinical studies indicate the importance of T cells in this infrequent phenomenon, these studies do not preclude that other immune mechanisms exhibit an addition role in the abscopal effect. We therefore addressed the question whether in addition to T cell mediated responses also humoral anti-tumour responses are modulated after fractionated RT and whether systemic dendritic cell (DC) stimulation can enhance tumour-specific antibody production. We selected the 67NR mammary carcinoma model since this tumour showed spontaneous antibody production in all tumour-bearing mice. Fractionated RT to the primary tumour was associated with a survival benefit and a delayed growth of a non-irradiated (contralateral) secondary tumour. Notably, fractionated RT did not affect anti-tumour antibody titers and the composition of the immunoglobulin (Ig) isot...
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A coordinated cellular interplay is of crucial importance in both host defense against pathogens and malignantly transformed cells. The various interactions of Dendritic Cells (DC), Natural Killer (NK) cells, and T helper (Th) cells can... more
A coordinated cellular interplay is of crucial importance in both host defense against pathogens and malignantly transformed cells. The various interactions of Dendritic Cells (DC), Natural Killer (NK) cells, and T helper (Th) cells can be influenced by a variety of pathogen-associated molecular patterns (PAMPs) and will lead to enhanced CD8+effector T cell responses. Specific Pattern Recognition Receptor (PRR) triggering during maturation enables DC to enhance Th1 as well as NK helper cell responses. This effect is correlated with the amount of IL-12p70 released by DC. Activated NK cells are able to amplify the proinflammatory cytokine profile of DC via the release of IFN-γ. The knowledge on how PAMP recognition can modulate the DC is of importance for the design and definition of appropriate therapeutic cancer vaccines. In this review we will discuss the potential role of specific PAMP-matured DC in optimizing therapeutic DC-based vaccines, as some of these DC are efficiently acti...
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The combination of melphalan, prednisone and thalidomide (MPT) is considered standard therapy for newly diagnosed patients with multiple myeloma (NDMM) who are ineligible for stem-cell transplantation. Long term treatment with thalidomide... more
The combination of melphalan, prednisone and thalidomide (MPT) is considered standard therapy for newly diagnosed patients with multiple myeloma (NDMM) who are ineligible for stem-cell transplantation. Long term treatment with thalidomide is hampered by neurotoxicity. Melphalan, prednisone and lenalidomide, followed by lenalidomide maintenance therapy showed promising results, without severe neuropathy emerging. We randomly assigned 668 NDMM patients, ineligible for stem-cell transplantation, between nine 4-weekly cycles of MPT followed by thalidomide maintenance until disease progression or unacceptable toxicity (MPT-T) and the same MP regimen with thalidomide being replaced by lenalidomide (MPR-R). This multicenter, open-label, randomised phase 3 trial was undertaken by HOVON and the NMSG. The primary endpoint was progression-free survival (PFS). The accrual for the study was completed in October 19, 2012. 318 patients were randomly assigned to receive MPT-T and 319 MPR-R. After a...
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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.... more
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 AL 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 (New England Journal of Medicine 358;1) 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 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 10 years from the date of transplantation. Twelve (12%) of patients died during induction t...
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Purpose We investigated whether bortezomib during induction and maintenance improves survival in newly diagnosed multiple myeloma (MM). Patients and Methods In all, 827 eligible patients with newly diagnosed symptomatic MM were randomly... more
Purpose We investigated whether bortezomib during induction and maintenance improves survival in newly diagnosed multiple myeloma (MM). Patients and Methods 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/m2 (PAD) once every 2 weeks for 2 years. The primary analysis was progression-free survival (PFS) adjusted for International Staging System (ISS) stage. Results 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 ...
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Research Interests: Biology, Medicine, Sequence Analysis, Humans, Male, and 12 moreKaryotyping, Middle Aged, Spectrum, Fluorescent in situ hybridization, Gene fusion, Septins, Base Sequence, Cell Cycle Proteins, DNA binding proteins, Acute Lymphoblastic Leukemia, Nephrotic syndrome, and reverse transcriptase polymerase chain reaction
Research Interests: Medicine, Low Dose, Mice, Haplotypes, Female, and 15 moreAnimals, Male, Progenitor Cells, Bone marrow, Fibroblast Growth Factor, Clinical Sciences, Mouse Model, Bone Marrow Transplantation, Gastrointestinal Tract, Dermatitis, Clinical Application, Hematopoietic Stem Cell Transplantation, Phosphate Buffer Saline, Gastrointestinal Diseases, and Acute Disease(Animals, Male, Progenitor Cells, Bone marrow, Fibroblast Growth Factor, Clinical Sciences, Mouse Model, Bone Marrow Transplantation, Gastrointestinal Tract, Dermatitis, Clinical Application, Hematopoietic Stem Cell Transplantation, Phosphate Buffer Saline, Gastrointestinal Diseases, and Acute Disease)
(Animals, Male, Progenitor Cells, Bone marrow, Fibroblast Growth Factor, Clinical Sciences, Mouse Model, Bone Marrow Transplantation, Gastrointestinal Tract, Dermatitis, Clinical Application, Hematopoietic Stem Cell Transplantation, Phosphate Buffer Saline, Gastrointestinal Diseases, and Acute Disease)
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Research Interests: Treatment Outcome, Stem Cell Transplantation, Humans, Negative Affect, Female, and 13 moreMultiple Myeloma, Male, Recurrence, Clinical Sciences, Aged, Middle Aged, Bone Marrow Transplantation, Adult, Survival Rate, Overall Survival, Progression Free Survival, Disease Free Survival, and Chromosome deletion
Simple Summary Natural killer (NK) cells are potent killers of tumor cells. Many tumors, including breast cancers, develop mechanisms to suppress anti-tumor immune responses, requiring the development of strategies to overcome... more
Simple Summary Natural killer (NK) cells are potent killers of tumor cells. Many tumors, including breast cancers, develop mechanisms to suppress anti-tumor immune responses, requiring the development of strategies to overcome suppression. Here, we tested a combination therapy that aims to (1) enhance NK cell activation and (2) reduce NK cell inhibition mediated by suppressive factors in tumors or in the tumor microenvironment. We cultured cell lines under hypoxia to mimic the tumor microenvironment or used patient-derived breast cancer cells that were primed by the patient’s tumor environment. Our results demonstrated that cytokine-activated NK cells remained active under hypoxia and that tumor-targeting antibodies enhanced the NK cell anti-breast cancer response. Moreover, we observed that NK cell suppression by inhibitory ligands on the tumor cells can be reduced by the selection of NK cell donors with NK receptors that are incompatible with these ligands. Collectively, we presen...
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Autologous haematopoietic stem-cell transplantation versus bortezomib–melphalan–prednisone, with or without bortezomib–lenalidomide–dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 s...more
Background: AL amyloidosis is generally caused by a kappa or lambda light-chain producing plasma cell clone in the bone marrow. High-dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) is effective in AL... more
Background: AL amyloidosis is generally caused by a kappa or lambda light-chain producing plasma cell clone in the bone marrow. High-dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) is effective in AL amyloidosis. Pretreatment of these patients with vincristine, doxorubicin and dexamethasone (VAD) may have a rapid and additive effect on the underlying plasma cell clone. Objective: To study the feasibility and efficacy of VAD followed by HDM and ASCT in AL amyloidosis. Patients and Methods: In a prospective multicenter phase II study, the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) studied the effect of three courses of VAD followed by HDM with ASCT on hematological and clinical response rates and overall survival in AL amyloidosis. Untreated patients aged ≤ 65 years with proven AL amyloidosis and monoclonal gammopathy or multiple myeloma stage I were included. Patients with recent prior malignancy, other types of amyloidosis, and severe other ...
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Background: Novel agents such as IMIDs and proteasome inhibitors have substantially changed the therapeutic landscape in the first line treatment of multiple myeloma (MM). Better response rates and prolonged progression-free survival have... more
Background: Novel agents such as IMIDs and proteasome inhibitors have substantially changed the therapeutic landscape in the first line treatment of multiple myeloma (MM). Better response rates and prolonged progression-free survival have lead to an improvement in overall survival (OS) with median values well beyond 5 years. Therefore to assess whether first line therapy strategies have an impact on the prognosis for patients with MM, long-term results of clinical trials with follow up covering >10 years are necessary. Methods: The HOVON-65/GMMG-HD4 study is a prospective randomized trial testing bortezomib+adriamycin+dexamethasone (PAD) for 3 cycles as induction prior to high-dose chemotherapy (HDT) and autologous stem cell transplantation compared to vincristine+adriamycin+dexamethasone (VAD) in the control arm. After one (HOVON) or two (GMMG) HDT maintenance was given for 2 years consisting of bortezomib every 2 weeks in the PAD arm and thalidomide 50 mg daily in the VAD arm. ...
Research Interests:
Introduction: Daratumumab (DARA) has potent single agent activity in relapsed/refractory multiple myeloma (RRMM). The effectivity of DARA is partially dependent on the expression of its target, CD38, on tumor cells. Upregulation of CD38... more
Introduction: Daratumumab (DARA) has potent single agent activity in relapsed/refractory multiple myeloma (RRMM). The effectivity of DARA is partially dependent on the expression of its target, CD38, on tumor cells. Upregulation of CD38 on MM cells by all-trans retinoic acid (ATRA) improved the ex vivo efficacy of DARA, even in DARA-resistant MM cells. We therefore evaluated the efficacy and safety of DARA combined with ATRA in RRMM patients in the DARA/ATRA study (NCT02751255). Methods: In part A of this prospective, multicenter phase 1/2 trial, DARA was administered according to the approved schedule (16 mg/kg; cycles 1-2: weekly; cycles 3-6: biweekly; cycles ≥7: monthly). In part B, ATRA was given twice daily during 3 days prior to each DARA infusion. DARA dosing was resumed according to the aforementioned schedule. Inclusion criteria were ≥2 prior lines of treatment, WHO performance score 0-2, adequate bone marrow reserve, kidney and hepatic function. Patients were enrolled in p...