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ABSTRACT: What is known and objective: High costs of novel agents increasingly put pressure on limited healthcare budgets. Demonstration of their real-world costs and cost-effectiveness is often required for reimbursement. However, few published economic evaluations of novel agents for multiple myeloma exist. Moreover, existing cost analyses were heavily based on conventionally treated patients. We investigated real-world health care costs of relapsed/refractory multiple myeloma in Dutch daily practice. Methods: A retrospective medical chart review was conducted for 139 patients treated between January 2001 and May 2009. Total monthly costs attributable to each cost component were described across all regimens and for bortezomib-, thalidomide- and lenalidomide-based treatment regimens. Results: Mean monthly total costs (€3,981) varied depending on the sequence of therapy (range: €442-€31,318). Significant cost drivers across all regimens included costs of therapy and hospital admissions. The acquisition costs for novel agents in particular accounted for 32% of mean total monthly costs. Prognostic factors associated with increased mean total monthly costs in multivariate regression analysis included low platelet counts (P = 0·01) and worsening performance status (P < 0·001). Mean total monthly costs of bortezomib- and lenalidomide-based regimens were significantly higher than those for thalidomide-based regimens in second, third and fourth treatment line. What is new and conclusions: Real-world costs during treatment of relapsed/refractory multiple myeloma vary greatly. Cost drivers include hospital admissions and acquisition costs of novel agents. Costs also vary by prognostic factors and treatment-related resource use. Future studies assessing the costs of combination therapy consisting of two or more novel agents are encouraged.
Journal of Clinical Pharmacy and Therapeutics 11/2012; · 1.57 Impact Factor
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ABSTRACT: Haematopoietic stem cell transplantation (SCT) is an expensive lifesaving procedure, which is increasingly performed in patients with haematological diseases. Developments in the protocol for SCT have resulted in cost estimates that require updating. We aimed to calculate actual costs for SCT and to identify major cost drivers by means of a daily practice cost study. We randomly selected 191 patients, treated at three university hospitals, who underwent an autologous (auto) SCT or allogeneic (allo) SCT in 2007, 2008 or 2009. Allo-SCT included sibling donors, matched unrelated donors (MUD) and umbilical cord blood (UCB). Resource use was collected from the hospital registration systems and medical files. The total costs included selection and harvesting of stem cells, transplantation and 1-year follow-up. The average costs per patient were 45,670 for auto-SCT and 101,919 for sibling allo-SCT. The costs of transplantations from unrelated donors were much higher: 171,478 for allo-SCT-MUD and 254,689 for allo-SCT-UCB. Hospital inpatient days together with laboratory and other activities were the main cost drivers across all types of SCT. Besides, donor search costs were a large cost component in allo-SCT-sib (18 %) and allo-SCT-MUD (12 %). Real-world costs were above routine reimbursement and appropriate financing is necessary to guarantee the continuation of SCT. The costs calculated in this study provide reliable up-to-date input for cost-effectiveness studies and budget revision.
Annals of Hematology 08/2012; · 2.62 Impact Factor
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ABSTRACT: Identifying factors that predict health-related quality of life (QOL) following hematopoietic SCT, is important in estimating patients' abilities to adjust to the consequences of their disease and treatment. As the studies that have been published on this subject are scattered, the present study aimed to systematically review prognostic factors for health-related QOL after auto- and allo-SCT in hematological malignancies. A systematic, computerized search in Medline, EMBASE, PsycINFO and the Cochrane Library was conducted from 2002 to June 2010. The methodological quality of the studies was assessed using an adaptation of Hayden's criteria list. Qualitative data synthesis was performed to determine the strength of the scientific evidence. In all, 35 studies fulfilled the selection criteria. Strong-moderate evidence was found for GVHD, conditioning regimen, being female, younger age, receiving less social support and pre-transplant psychological distress as predictors of various aspects of health-related QOL following hematopoietic SCT. The results of this review may help transplant teams in selecting patients at risk for experiencing a diminished health-related QOL following hematopoietic SCT. Follow-up treatment can be provided in order to promote QOL.
Bone marrow transplantation 07/2011; 47(6):757-69. · 3.00 Impact Factor
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G J Tack,
M J Wondergem,
A Al-Toma,
W H M Verbeek,
A Schmittel,
M V Machado,
F Perri,
G J Ossenkoppele, P C Huijgens,
M W J Schreurs,
C J J Mulder,
O J Visser
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ABSTRACT: Autologous hematopoietic SCT (auto-SCT) has been effective therapy for refractory disease, in both malignancies and severe autoimmune diseases. It seems feasible and safe for refractory celiac disease (RCD) type II, although long-term results have not been evaluated yet. With current therapies, progression into enteropathy-associated T-cell lymphoma (EATL) occurs in 60-80% patients, with a high mortality rate. Therefore, it is important to evaluate new treatment strategies. Between March 2004 and February 2010, 18 RCD II patients were evaluated for auto-SCT preceded by conditioning with fludarabine and melphalan, as a consequence of unresponsiveness to cladribine therapy. Adverse events, survival rate, EATL development and change in clinical, histological and immunological course were monitored. Thirteen patients were transplanted successfully and followed up for >2 years, 4-year survival rate was 66%. Only one patient died because of transplant-related complications. The majority of patients showed an impressive clinical improvement and five a complete histological remission. In five patients, auto-SCT could not be performed; they all died with a median survival of 5.5 months. EATL was observed in one transplanted patient, only after 4 years of follow-up. Auto-SCT after conditioning with high-dose chemotherapy in RCD II patients unresponsive to cladribine therapy is feasible and seems promising.
Bone marrow transplantation 06/2011; 46(6):840-6. · 3.00 Impact Factor
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Bone marrow transplantation 10/2009; 45(5):959-60. · 3.00 Impact Factor
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ABSTRACT: The selective uptake of the Auger- and internal conversion electrons emitting radionuclide 67Ga in maligant tumours may have therapeutic potential. We studied several factors which might affect the uptake and radiotoxicity of 67Ga in the human lymphoma cell line U-715. The 67Ga uptake was dependent on transferrin in a dose-dependent manner. The highest 67Ga uptake was found in the presence of 50 µg/ml purified human transferrin. Serum components other than transferrin negatively influenced the 67Ga uptake. Cells were adapted to a serum-free medium in which cells could be maintained for months and without factors disturbing 67Ga uptake. We demonstrated that there was a positive correlation between cell viability and 67Ga uptake (r = 0·97). Preculturing of cells in iron- and transferrin-deficient medium prior to 67Ga uptake led to upregulation of the transferrin receptor and a three-fold increase of 67Ga uptake. Uptake in these cells could be blocked by 72% by anti-transferrin-receptor monoclonal antibodies. Autoradiography of U-715 cells after 67Ga incubation showed intracellular 67Ga both in the cytoplasm and nucleus. Cell fractionation of 67Ga-loaded cells showed 27% of 67Ga present in the nuclei. Culturing of cells for 4 days in the presence of 3 MBq/ml 67Ga resulted in a 45% decrease of cell proliferation. The clonogenic capacity was diminished by 91%. In conclusion, we have demonstrated that 67Ga uptake is a transferrin-receptor-dependent mechanism of vital cells, and that after uptake 67Ga enters the cytosol and nucleus and has a strong cytotoxic effect on clonogenic capacity.
07/2009; 64(6):749-759.
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ABSTRACT: Cyclooxygenase activity in human platelets reappears after ingestion of aspirin as a function of the platelet production rate. In different studies the activity reappeared without delay or with an interval of at least 48 h after stopping the drug. Because inhibition of megakaryocyte cyclooxygenase is the sole likely explanation for a delay we determined thromboxane B2 in human megakaryocytes obtained under local anaesthesia. We found that aspirin does not inhibit human megakaryocytes in vivo but does so in vitro. Therefore, it does not seem likely that there is actually a delay in platelet cyclooxygenase resurgence after aspirin intake. In order to suppress platelet cyclooxygenase constantly, aspirin should be given once or twice a day and not once or twice a week.
European Journal Of Haematology 04/2009; 36(1):92 - 95. · 2.61 Impact Factor
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ABSTRACT: A 21-year-old male presented with a widespread skin infiltration characterized by irregularly elevated blue-red plaques, generalized lymphadenopathy and enlarged parotid glands. Histological examination of the skin showed the characteristics of Lennert's lymphoma, as did the lymph nodes and parotid glands.Immunological studies on lymph node tissue revealed normal amounts of B- and T-cells. The B-cells were polyclonal. The T-cells showed functional impairment in culture.Treatment with prednisone resulted in complete disappearance of all tumour manifestations within 6 weeks.
European Journal Of Haematology 04/2009; 24(5):430 - 434. · 2.61 Impact Factor
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ABSTRACT: 3 commonly used parameters for platelet aggregability were tested for their dependence on citrate concentrations. Relatively minor changes in citrate concentrations markedly influenced ADP threshold values for secondary aggregation. Collagen induced platelet malondialdehyde (MDA) production was reduced by increasing the citrate level. This effect was still present in plasma which was also anticoagulated with EDTA. Thrombin induced MDA production was considerably higher in EDTA than in citrate plasma. Citrate appears to inhibit aggregation as well as MDA synthesis. The latter effect does not seem to be solely caused by the effect of citrate on ionized calcium levels.
European Journal Of Haematology 04/2009; 31(2):129 - 132. · 2.61 Impact Factor
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ABSTRACT: The aim of the present study was to identify trends in numbers of European patients treated with autologous and allogeneic haematopoietic stem cell transplantation (HSCT) as well as to provide anticipated transplant rates for the upcoming years. The following indications were considered: haematological malignancies (acute leukaemias, myeloproliferative disorders, lymphoproliferative disorders and multiple myeloma), solid tumours and non-malignant diseases. Numbers of patients treated from 1990 to 2004 were extracted from the European Group for Blood and Marrow Transplantation database, extrapolated to 2012 using mathematic models and adjusted to the literature study and expert opinion. In Europe, a 13% raise in HSCT utilisation is to be expected from 2005 to 2010, mostly due to the growing application of reduced-intensity conditioning regimens followed by allogeneic HSCT. Growing transplant rates are likely to exert health expenditure budgets and put pressure on health care providers and health insurers in Europe. Therefore, the rapid expansion would ideally imply a simultaneous increase in HSCT budgets.
European Journal of Cancer 12/2007; 43(16):2359-65. · 5.54 Impact Factor
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ABSTRACT: Despite treatment, enteropathy-associated T-cell lymphoma has a very poor outcome. Chemotherapy can be complicated by small bowel perforation, gastrointestinal bleeding and development of enterocolic fistulae. Here we report on the feasibility, safety and efficacy of high-dose chemotherapy followed by autologous stem cell transplantation in patients with enteropathy-associated T-cell lymphoma (three upfront and one at relapse), with or without prior partial small bowel resection.
Four patients [two males, two females, mean age 65 years (range 60-69 years)] received high-dose chemotherapy followed by autologous stem cell transplantation. Partial small bowel resection has been performed in three patients.
All four patients completed the mobilization and leucopheresis procedures successfully and subsequently received conditioning chemotherapy and transplantation. Engraftment occurred in all patients. No major non-haematological toxicity or transplantation-related mortality was observed. One patient has ongoing complete remission 32 months after transplantation. Three patients died from relapse within few months after autologous stem cell transplantation.
Autologous stem cell transplantation seems unsatisfactory for patients with enteropathy-associated T-cell lymphoma. More intensive conditioning and aggressive chemotherapy with/or without targeted immunotherapy as well as allogenous stem cell transplantation needs to be explored.
Digestive and Liver Disease 08/2007; 39(7):634-41. · 3.05 Impact Factor
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ABSTRACT: An open-label randomised clinical trial was designed to compare the efficacy and tolerance of levofloxacin and ciprofloxacin plus phenethicillin for the prevention of bacterial infections in patients with high-risk neutropenia, and to monitor the emergence of antimicrobial resistance. Adult patients (n = 242) scheduled to receive intensive treatment for haematological malignancies were assigned randomly to receive oral prophylaxis with either levofloxacin 500 mg once-daily (n = 122), or ciprofloxacin 500 mg twice-daily plus phenethicillin 250 mg four-times-daily (n = 120). The primary endpoint was failure of prophylaxis, defined as the first occurrence of either the need to change the prophylactic regimen or the initiation of intravenous broad-spectrum antibiotics. This endpoint was observed in 89 (73.0%) of 122 levofloxacin recipients and in 85 (70.8%) of 120 ciprofloxacin plus phenethicillin recipients (RR 1.03, 95% CI 0.88-1.21, p 0.71). No differences were noted between the two groups with respect to secondary outcome measures, including time to endpoint, occurrence of fever, type and number of microbiologically documented infections, and administration of intravenous antibiotics. A questionnaire revealed that levofloxacin was tolerated significantly better than ciprofloxacin plus phenethicillin. Surveillance cultures indicated the emergence of viridans group (VG) streptococci resistant to levofloxacin in 17 (14%) of 122 levofloxacin recipients; in these cases, the prophylactic regimen was adjusted. No bacteraemia with VG streptococci occurred. It was concluded that levofloxacin and ciprofloxacin plus phenethicillin are equally effective in the prevention of bacterial infections in neutropenic patients, but that levofloxacin is tolerated better. Emergence of levofloxacin-resistant VG streptococci is of concern, but appears to be a manageable problem.
Clinical Microbiology and Infection 06/2007; 13(5):497-503. · 4.54 Impact Factor
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ABSTRACT: There is increasing interest in the use of stem cells for therapeutic purposes. The use of embryonic stem cells carries ethical and legal restrictions that limit their role in tissue regeneration. These restrictions do not apply to somatic stem cells, such as haematopoietic stem cells, which normally reside in the bone marrow. Preclinical studies have produced very promising results using these cells in experimental models of myocardial infarction. Bone-marrow cells have also been used to generate several different types of tissue. However, experimental data suggest that bone marrow also houses other non-haematopoietic stem cells, which could account for the alleged plasticity of haematopoietic stem cells. So far, the results of randomised clinical trials in patients with myocardial infarction or heart failure have been disappointing. It is clear that further research in this field is needed.
Nederlands tijdschrift voor geneeskunde 08/2006; 150(27):1494-6.
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ABSTRACT: Radio-immunotherapy is a new treatment modality for patients with B-cell non-Hodgkin lymphoma. In radio-immunotherapy, a therapeutic radionuclide is coupled to a monoclonal antibody directed against a tumour-specific or tumour-associated antigen. Biodistribution studies and dosimetry are used in the planning of radio-immunotherapy. Clinical studies, notably in patients with indolent non-Hodgkin lymphoma, have demonstrated the clinical feasibility and efficacy of this treatment. The use of a high dose ofradio-immunotherapy in combination with (high-dose) chemotherapy and peripheral stem-cell transplantation constitutes a supplemental treatment for patients who respond insufficiently or not at all to standard therapy. The exact place of radio-immunotherapy in the treatment of patients with non-Hodgkin lymphomas is not yet clear.
Nederlands tijdschrift voor geneeskunde 11/2005; 149(42):2324-8.
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ABSTRACT: In order to calibrate his haemoglobin meter, a general practitioner had his own haemoglobin level checked regularly at a nearby laboratory. At 37 years of age, one of these assays revealed 7,0 mmol/l. Because he had no symptoms, he prescribed himself iron-substitution therapy but the haemoglobin concentration did not normalise. At 52 years of age, the patient increasingly suffered from fatigue and exertional dyspnoea and had intermittent abdominal pain, distension and rumbling. Biopsies of the small intestine revealed crypt hypertrophy and intraepithelial lymphocytosis: signs ofcoeliac disease. The symptoms disappeared when the patient started to use a gluten-free diet. The haemoglobin level also normalised. Coeliac disease must be considered in the differential diagnosis of iron-deficiency anaemia.
Nederlands tijdschrift voor geneeskunde 05/2005; 149(15):801-7.
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ABSTRACT: The treatment for multiple myeloma has undergone many changes over the past decade. Intensive therapy with autologous stem-cell support has improved the clinical outcome significantly in younger patients. Reduced intensity conditioning regimens have lowered the high treatment-related mortality of myeloablative allogeneic transplantation. New effective anti-myeloma drugs such as bortezomib and thalidomide analogues have become available. These new developments have made it necessary to formulate recommendations to facilitate decisions concerning the management of myeloma patients. The Myeloma Working Party of the Dutch Haemato-Oncology Association (Stichting Haemato-Oncologie voor Volwassenen Nederland) has developed therapy guidelines based on phase-II and phase-III studies as well as the expertise of the working party. These include upfront induction therapy followed by autologous transplantation for patients aged up to 65 years and oral melphalanprednisone treatment for patients with severe co-morbidities and patients over the age of 65 years. Patients under the age of 66 with an HLA-identical (family) donor are candidates for non-myeloablative stem-cell transplantation following autologous stem-cell transplantation. For second-line treatment, thalidomide, combined with dexamethasone is recommended. Younger patients responding to second-line treatment are candidates for a second autologous transplant. Bortezomib is indicated for those patients refractory to the previous two lines of treatment. All patients should receive long-term bisphosphonates. Erythropoietin may be considered in symptomatic anaemia as well as antibiotic prophylaxis during induction therapy which includes dexamethasone.
Nederlands tijdschrift voor geneeskunde 05/2005; 149(15):808-13.
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ABSTRACT: To determine the incremental cost-effectiveness ratio (ICER) of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) vs. CHOP plus rituximab (R-CHOP) in diffuse large B-cell lymphoma (DLBCL) patients in the Netherlands.
A state transition model was developed to estimate the clinical course, costs and quality of life of patients with stage II, III or IV DLBCL receiving initial treatment with CHOP or R-CHOP to arrive at the ICER. The base year for the cost analysis was 2002 and was performed from the societal perspective. Only direct medical costs were included. The time horizon of the model was 15 yr and both costs and effects were discounted at 4%. Sensitivity analyses were performed to determine the effect of varying base-line assumptions of the model.
The incremental gain in quality adjusted life years (QALYs) was 0.88 in both the younger and the older patient groups. The costs were 12 343 higher in the younger group of patients and 15 860 in the older patients. This resulted in an ICER of 13 983 for the younger and 17 933 for the older patients per QALY gained. These results were sensitive to the time horizon of the model, other variations had a marginal impact on the outcome.
The addition of rituximab to standard therapy for DLBCL results in a gain of 0.88 QALYs. The ICER of 13 983 for younger and 17 933 for older patients per QALY gained should, seen in the light of disease severity, be considered acceptable by most policy makers in priority setting for budget allocation.
European Journal Of Haematology 04/2005; 74(3):194-202. · 2.61 Impact Factor
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ABSTRACT: This study describes the natural course of vincristine-induced peripheral neuropathy in patients with lymphoma (n = 114) receiving vincristine in two different dose intensities. Neuropathic changes were observed in both dose intensity groups, but the higher dose intensity group reported significantly more symptoms during therapy, whereas neurologic signs were significantly more prominent after a cumulative dose of 12 mg vincristine. Furthermore, off-therapy worsening of symptoms (24%) and signs (30%) occurred unexpectedly.
Neurology 04/2005; 64(6):1076-7. · 8.31 Impact Factor
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ABSTRACT: To investigate the subjective well-being of patients with newly diagnosed multiple myeloma who were treated in a tandem transplantation programme.
Fifty-one patients participated in the prospective, longitudinal questionnaire study. The EORTC QLQ-C30 and the EuroQol-5D were administered 2 wk after completion of vincristine, adriamycin and dexamethason/vincristine, adriamycin and methyl prednison (VAD/VAMP) chemotherapy, both at hospital discharge after treatment with high-dose melphalan (HDM) and 1 month after this hospital discharge, at hospital admission, at the day of hospital discharge for peripheral stem cell transplantation (PSCT) and at 6 and 12 months following discharge after PSCT.
Overall, patients' functioning improved during treatment and follow-up, with significant decreases shortly following PSCT. Shortly after HDM and PSCT, patients reported a considerable increase in levels of soreness in the mouth (+26/+36 points on a scale ranging form 0 to 100; P < 0.01), change of taste (+23/+21 points; P < 0.05/NS), nausea/vomiting (+26/+27 points; P < 0.01/< 0.05), appetite loss (+40/+43 points; P < 0.001) and diarrhoea (+25/+36 points; P < 0.01). However, none of these symptoms persisted during follow-up.
The intensive treatment programme was subjectively being well tolerated by the majority of patients. The duration of declined quality of life after administration of HDM seemed to be short. The duration of subjective recovery after PSCT remained uncertain, but in any case was present at the 6 month follow-up. Together with the rather good results in survival, the evaluation of quality of life invites further exploration of double transplantations in multiple myeloma.
European Journal Of Haematology 03/2005; 74(2):136-43. · 2.61 Impact Factor
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ABSTRACT: Allogeneic stem cell transplantation is a potentially curative procedure for patients with haematological malignancies. Conventional, myeloablative conditioning is, however, poorly tolerated by patients of advanced age, those receiving second transplants and those with concomitant diseases. Based on recognition of the importance of a graft-versus-disease (GVD) effect in curing malignant haematological disease, reduced intensity conditioning (RIC) as preparation for allogeneic stem cell transplantation has been developed for these patients. Although large prospective randomised clinical trials with significant follow-up are lacking, transplant-related morbidity and mortality of RIC transplants seem to compare favourably with conventional conditioning in this group of patients.
The Netherlands Journal of Medicine 03/2005; 63(2):43-51. · 2.07 Impact Factor
