R-CODOX-M/R-IVAC versus DA-EPOCH-R in patients with newly diagnosed Burkitt lymphoma (HOVON/SAKK): final results of a multicentre, phase 3, open-label, randomised trial.

BACKGROUND: Patients with newly diagnosed high-risk Burkitt lymphoma are treated with high-intensity immune-chemotherapy regimens such as R-CODOX-M/R-IVAC or with lower-intensity regimens such as DA-EPOCH-R. The aim of this study was to make a formal comparison between these regimens. METHODS: This multicentre, phase 3, open-label, randomised study was done in 26 clinical centres in the Netherlands, Belgium, and Switzerland. Eligible patients were aged 18-75 years with newly diagnosed high-risk Burkitt lymphoma without CNS involvement. Patients were randomly assigned to two cycles of R-CODOX-M/R-IVAC (R-CODOX-M: rituximab 375 mg/m2 on day 1 and 9, cyclophosphamide 800 mg/m2 on day 1, cyclophosphamide 200 mg/m2 on days 2-5, vincristine 1·5 mg/m2 on days 1 and 8, doxorubicin 40 mg/m2 on day 1, and methotrexate 3000 mg/m2 on day 10; R-IVAC: rituximab 375 mg/m2 on days 3 and 7, iphosphamide 1500 mg/m2 on days 1-5, etoposide 60 mg/m2 on days 1-5, and cytarabin 2000 mg/m2 on day 1 and 2) or six cycles of DA-EPOCH-R (dose-adjusted etoposide 50-124 mg/m2 on days 1-4, prednisolone 120 mg/m2 on days 1-5, vincristine 0·4 mg/m2 on days 1-4, dose-adjusted cyclophosphamide 480-1866 mg/m2 on day 5, dose-adjusted doxorubicin 10-24·8 mg/m2 on days 1-4, rituximab 375 mg/m2 on days 1 and 5). Patients older than 65 years received a dose modified R-CODOX-M/R-IVAC. All drugs were intravenous except for prednisolone, which was oral. Patients also received four intrathecal CNS administrations with cytarabin (70 mg) and four with methotrexate (15 mg). Patients were stratified by centre, leukemic disease, and HIV-positivity. The primary endpoint was progression-fee survival. All analyses were done by modified intention-to-treat, excluding randomly assigned patients who were subsequently found to have CNS involvement or diagnosis other than Burkitt lymphoma at study entry. This study is registered with the European Clinical Trial Register, EudraCT2013-004394-27. FINDINGS: Due to a slow accrual, the study was closed prematurely on Nov 15, 2021. Between Aug 4, 2014, and Sept 17, 2021, 89 patients were enrolled and randomly assigned to receive R-CODOX-M/R-IVAC (n=46) or DA-EPOCH-R (n=43). Five patients were excluded after random assignment (three in the R-CODOX-M/R-IVAC group [one diagnosis other than Burkitt lymphoma at study entry according to local pathology and two CNS involvement] and two in the DA-EPOCH-R group [one diagnosis other than Burkitt lymphoma at study entry according to local pathology and one CNS involvement]. 84 remaining patients were included in the modified intention-to-treat analysis. 73 (87%) of 84 patients were male, 76 (90%) presented with stage III or IV disease, and nine (11%) had HIV-positive Burkitt lymphoma. Median patient age was 52 years (IQR 37-64). With a median follow-up of 28·5 months (IQR 13·2-43·7), 2-year progression-free survival was 76% (95% CI 60-86%) in the R-CODOX-M/R-IVAC group and 70% (54-82%) in the DA-EPOCH-R group (hazard ratio 1·42, 95% CI 0·63-3·18; p=0·40). There were two deaths in the R-CODOX-M/R-IVAC group (one infection [treatment related] and one due to disease progression [not treatment related]) and one death in the DA-EPOCH-R group (COVID-19 infection [treatment related]). In the R-CODOX-M/R-IVAC group, four patients went off-protocol because of toxic effects, versus none in the DA-EPOCH-R group. Patients treated with R-CODOX-M/R-IVAC had more infectious adverse events (24 [56%] of 43 patients had at least one grade 3-5 infection vs 14 [34%] of 41 patients in the DA-EPOCH-R group). INTERPRETATION: The trial stopped early, but the available data suggest that while DA-EPOCH-R did not result in superior progression-free survival compared with R-CODOX-M/R-IVAC, it was associated with fewer toxic effects and need for supportive care. DA-EPOCH-R appears to be an additional valid therapeutic option for patients with high-risk Burkitt lymphoma without CNS involvement. FUNDING: The Dutch Cancer Society and the Schumacher-Kramer Foundation.

Rationale and development of an e-health application to deliver patient-centered care during treatment for recently diagnosed multiple myeloma patients: pilot study of the MM E-coach.

BACKGROUND: Patients with multiple myeloma (MM) increasingly face complicated treatment regimens. E-health may support patients and healthcare providers in enhancing a patient-centered healthcare approach. Therefore, we aimed to develop a patient-centered multi-modality e-health application, to assess the application for usability and end-user experiences. METHODS: The application was developed following an iterative "action-based" methodology using the design thinking approach. Key end users participated, and relevant stakeholders were consulted in the development process. First, the care pathway was evaluated, the focus of development was determined, and a solution ideated during recurring multidisciplinary meetings. Second, a prototype was tested and improved. Third, a subsequent prototype was evaluated during a pilot study with patients and healthcare professionals on usability, usage, and experiences. RESULTS: The multi-modality application, named the "MM E-coach," consisted of a newly developed medication module, patient-reported outcome (PRO) questionnaire assessments, a messaging service, alerts, information provision, and a personal care plan. The median system usability score was 60 on a scale of 0-100. Patients appreciated the medication overview, healthcare professionals appreciated the outpatient clinic preparation module, and both appreciated the messaging service. Additional recommendations for improvement mostly revolved around the flexibility of functionalities and look and feel of the application. CONCLUSIONS: The MM E-coach has the potential to provide patient-centered care by supporting patients and caregivers during MM treatment and is a promising application to be implemented in the MM care pathway. A randomized clinical trial was initiated to study its clinical effectiveness.

Comparison of the CollaboRATE and SDM-Q-9 questionnaires to appreciate the patient-reported level of shared decision-making.

OBJECTIVE: To compare CollaboRATE and SDM-Q-9 questionnaires when appreciating patient-perceived level of shared decision-making (SDM) in doctor-patient consultations. METHODS: Data were harvested from five separate studies on SDM, conducted in three university and one large community hospital in the Netherlands, using Dutch versions of both questionnaires. CollaboRATE and SDM-Q-9 scores were expressed as percentages. Correlation was assessed using Spearman's Rho coefficient. Bland&Altman analysis was used to assess the degree of agreement. Top scores were calculated to assess possible ceiling effects. RESULTS: The five studies included 442 patients. Median CollaboRATE scores (88.9%, IQR 81.5-100%) were significantly higher (p < 0.001) than SDM-Q-9 scores (80.0%, IQR 64.4-100%). Correlation was moderate (Rho=0.53, p < 0.001). A systematic, 12.5-point higher score was found across the range of scores when using CollaboRATE. Top scores for CollaboRATE and SDM-Q-9 were present in 37.5% and 17% of questionnaires, respectively. CONCLUSIONS: Overall, CollaboRATE and SDM-Q-9 questionnaires showed a high level of patient-perceived SDM. However, CollaboRATE only moderately correlated with SDM-Q-9 and had a stronger ceiling effect. PRACTICE IMPLICATIONS: When choosing a SDM-measurement tool, its benefits and limitations should be weighed. These metrics should be combined with objective scores of SDM, as these may differ from the patients' subjective interpretation.

[Updated Dutch law demands shared decision-making]. / Meer 'samen beslissen' nodig door aangescherpte Wgbo.

In January 2020, the Dutch law on the medical treatment agreement was updated. In this update, shared decision-making is explicitly mentioned as a prerequisite during doctor-patient encounters. This entails explicit exploration of the patient's wishes, views and preferences and their integration in medical decision-making. There is growing interest in shared decision-making from patient advocacy and professional societies, the government, and healthcare insurers. However, both care professionals and patients are not yet used to applying this in their encounters. Creating awareness, training and organisational changes are essential aspects to foster shared decision-making. Various (umbrella) organisations in healthcare have developed (digital) tools for both care professionals and patients to support shared decision-making. This article addresses these tools to nudge all stakeholders towards shared decision-making.

Ixazomib, Daratumumab, and Low-Dose Dexamethasone in Frail Patients With Newly Diagnosed Multiple Myeloma: The Hovon 143 Study.

PURPOSE: Frail patients with newly diagnosed multiple myeloma have an inferior outcome, mainly because of a high discontinuation rate due to toxicity. We designed a phase II trial specifically for frail patients, evaluating the efficacy and tolerability of ixazomib-daratumumab-low-dose-dexamethasone (Ixa-Dara-dex). METHODS: Sixty-five patients, who were frail according to the International Myeloma Working Group frailty index, were treated with nine induction cycles Ixa-Dara-dex followed by maintenance with Ixa-Dara for a maximum of 2 years. RESULTS: The overall response rate on induction therapy was 78%. After a median follow-up of 22.9 months, median progression-free survival (PFS) was 13.8 months and 12-month overall survival (OS) was 78%. Median PFS and 12-month OS were 21.6 months and 92% in patients who were frail based on age > 80 years alone, versus 13.8 months and 78%, and 10.1 months and 70% in patients who were frail based on additional frailty parameters either ≤ 80 or > 80 years of age, respectively. In 51% of patients, induction therapy had to be discontinued prematurely, of which 6% because of noncompliance to study treatment, 9% because of toxicity, and 9% because of death (8% within 2 months, of which 80% because of toxicity). Quality of life improved during induction treatment, being clinically meaningful already after three induction cycles. CONCLUSION: Ixa-Dara-dex lead to a high response rate and improved quality of life. However, treatment discontinuation because of toxicity and early mortality, negatively influencing PFS and OS, remains a concern in frail patients. The outcome was heterogeneous across frail subpopulations. This should be taken into account in the design and interpretation of future studies in frail patients, to pave the way for more precise treatment guidance.

Developing a patient portal for haematology patients requires involvement of all stakeholders and a customised design, tailored to the individual needs.

BACKGROUND: Electronic patient portals are increasingly being implemented, also in (haemato) oncology. However, portal usage is low and depends on user and provider engagement. We explored wishes, expectations and thoughts of patients with a haematologic malignancy and their physicians with regard to the electronic patient portal. METHODS: Based on insights from literature and a focus group discussion we built a 44-item questionnaire. This questionnaire was spread amongst patients with a haematologic malignancy at the outpatient clinic that was not yet exposed to patient portal facilities. Haematologists completed a questionnaire based on literature. RESULTS: Patients were interested in many different types of access to information and portal functionalities. However, their opinions varied about the provision of access to the portal to other people, the role of the physician, possibilities for communication via the portal and timing of access. The physicians acknowledged the relevance of the electronic patient portal, but had some worries about the patients' autonomous information handling, organizational and technical issues. Patients frequently expressed to be open about the potential of the patient portal to orchestrate their care. Nevertheless, most physicians appreciated their supporting role towards the patient. CONCLUSIONS: Patients and physicians appreciated the electronic patient portal. Both groups need to be involved in further portal development to improve engagement by meeting patients' wishes, taking into account organizational and professional issues and managing expectations for both parties. To fit various patient profiles, portal design should be flexible and individualized. Further research should focus on the perceived added value and the impact on patient related outcome measures of portals.

Treatment continuation of four long-acting antipsychotic medications in the Netherlands and Belgium: A retrospective database study.

Achieving greater continuation of treatment is a key element to improve treatment outcomes in schizophrenia patients. However, reported treatment continuation can differ markedly depending on the study design. In a retrospective setting, treatment continuation remains overall poor among patients using antipsychotics. This study aimed to document the difference in treatment continuation between four long-acting injectable antipsychotics based on the QuintilesIMS LRx databases, national, longitudinal, panel based prescription databases of retail pharmacies, in the Netherlands and Belgium. Paliperidone palmitate once monthly, risperidone microspheres, haloperidol decanoate, and olanzapine pamoate were studied. This study demonstrated significantly higher treatment continuation of paliperidone palmitate once monthly compared to risperidone microspheres (p-value<0,01) and haloperidol decanoate (p-value<0,01) in both countries, a significantly higher treatment continuation of paliperidone palmitate once monthly compared to olanzapine pamoate in the Netherlands (p-value<0,01), and a general trend towards better treatment continuation versus olanzapine pamoate in Belgium. Analysing the subgroup of patients without previous exposure to long-acting antipsychotic treatment revealed the positive impact of previous exposure on treatment continuation with a subsequent long acting treatment. Additionally, the probability of restarting the index therapy was higher among patients treated with paliperidone palmitate once monthly compared to patients treated with risperidone microspheres and haloperidol decanoate. The data source used and the methodology defined ensured for the first time a comparison of treatment continuation in a non-interventional study design for the four long-acting injectable antipsychotics studied.

The Use of Continuous Treatment Versus Placebo or Intermittent Treatment Strategies in Stabilized Patients with Schizophrenia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials with First- and Second-Generation Antipsychotics.

BACKGROUND: Although continuous treatment with antipsychotics is still recommended as the gold standard treatment paradigm for all patients with schizophrenia, some clinicians question whether continuous antipsychotic treatment is necessary, or even justified, for every patient with schizophrenia who has been stabilized on antipsychotics. OBJECTIVE: The primary objectives of this systematic review and meta-analysis were (i) to compare relapse/hospitalization risks of stabilized patients with schizophrenia under active versus intermittent or placebo treatment conditions; (ii) to examine the role of several study characteristics, possibly intervening in the relationship between relapse risk and treatment condition; and (iii) to examine whether time to relapse is associated with antipsychotic treatment duration. METHODS: A systematic literature search, using the MEDLINE database (1950 until November 2014), was conducted for English-language published randomized controlled trials, covering a follow-up time period of at least 6 months, and investigating relapse/rehospitalization and/or time-to-relapse rates with placebo or intermittent treatment strategies versus continuous treatment with oral and long-acting injectable first- or second-generation antipsychotics (FGAs/SGAs) in stabilized patients with schizophrenia. Additional studies were identified through searches of reference lists of other identified systematic reviews and Cochrane reports. Two meta-analyses (placebo versus continuous and intermittent versus continuous treatment) were performed to obtain an optimal estimation of the relapse/hospitalization risks of stabilized patients with schizophrenia under these treatment conditions and to assess the role of study characteristics. For time-to-relapse data, a descriptive analysis was performed. RESULTS: Forty-eight reports were selected as potentially eligible for our meta-analysis. Of these, 21 met the inclusion criteria. Twenty-five records, identified through Cochrane and other systematic reviews and fulfilling the inclusion criteria, were added, resulting in a total of 46 records. Stabilized patients with schizophrenia who have been exposed for at least 6 months to intermittent or placebo strategies, respectively, have a 3 (odds ratio [OR] 3.36; 95% CI 2.36-5.45; p < 0.0001) to 6 (OR 5.64; 95% CI 4.47-7.11; p < 0.0001) times increased risk of relapse, compared with patients on continuous treatment. The availability of rescue medication (p = 0.0102) was the only study characteristic explaining systematic differences in the OR for relapse between placebo versus continuous treatment across studies. Studies reporting time-to-relapse data show that the time to (impending) relapse is always significantly delayed with continuous treatment, compared with placebo or intermittent treatment strategies. Although the interval between treatment discontinuation and symptom recurrence can be highly variable, mean time-to-relapse data seem to indicate a failure of clinical stability before 7-14 months with intermittent and before 5 months with placebo treatment strategies. For all reports included in this systematic review, median time-to-relapse rates in the continuous treatment group were not estimable as <50% of the patients in this treatment condition relapsed before the end of the study. CONCLUSIONS: With continuous treatment, patients have a lower risk of relapse and remain relapse free for a longer period of time compared with placebo and intermittent treatment strategies. Moreover, 'success rates' in the intermittent treatment conditions are expected to be an overestimate of actual outcome rates. Therefore, continuous treatment remains the 'gold standard' for good clinical practice, particularly as, until now, only a few and rather general valid predictors for relapse in schizophrenia are known and subsequent relapses may contribute to functional deterioration as well as treatment resistance in patients with schizophrenia.

GWATCH: a web platform for automated gene association discovery analysis.

BACKGROUND: As genome-wide sequence analyses for complex human disease determinants are expanding, it is increasingly necessary to develop strategies to promote discovery and validation of potential disease-gene associations. FINDINGS: Here we present a dynamic web-based platform - GWATCH - that automates and facilitates four steps in genetic epidemiological discovery: 1) Rapid gene association search and discovery analysis of large genome-wide datasets; 2) Expanded visual display of gene associations for genome-wide variants (SNPs, indels, CNVs), including Manhattan plots, 2D and 3D snapshots of any gene region, and a dynamic genome browser illustrating gene association chromosomal regions; 3) Real-time validation/replication of candidate or putative genes suggested from other sources, limiting Bonferroni genome-wide association study (GWAS) penalties; 4) Open data release and sharing by eliminating privacy constraints (The National Human Genome Research Institute (NHGRI) Institutional Review Board (IRB), informed consent, The Health Insurance Portability and Accountability Act (HIPAA) of 1996 etc.) on unabridged results, which allows for open access comparative and meta-analysis. CONCLUSIONS: GWATCH is suitable for both GWAS and whole genome sequence association datasets. We illustrate the utility of GWATCH with three large genome-wide association studies for HIV-AIDS resistance genes screened in large multicenter cohorts; however, association datasets from any study can be uploaded and analyzed by GWATCH.

Clinical outcomes of long-acting risperidone in recent versus long-term diagnosed Belgian schizophrenic patients: results from electronic Schizophrenia Treatment Adherence Registry (e-STAR) and Trial for the Initiation and Maintenance Of REmission in Schizophrenia with risperidone (TIMORES).

AIM: Potential differences in psychiatric clinical outcomes and hospitalization rates before and after the initiation of long-acting risperidone among recently and long-term diagnosed schizophrenia patients were studied. METHODS: Data from two observational studies (Trial for the Initiation and Maintenance Of REmission in Schizophrenia with risperidone (TIMORES) and electronic Schizophrenia Treatment Adherence Registry (e-STAR)) were categorized by the recency of their diagnose and compared in several post hoc analyses. Clinical Global Impression of illness Severity (CGI-S) and Global Assessment of Functioning (GAF) scores, as well as symptoms of clinical deterioration (including hospitalization data) at baseline, 12-month (for TIMORES and e-STAR) and 24-month (for e-STAR) follow-up were analysed. Other outcome measures included discontinuation rate, employment status and remission attainment. RESULTS: Statistically significantly differences between recent and long-term diagnosed schizophrenic patients at 12- and 24-month follow-up were found for CGI-S (between P < 0.01 and P ≤ 0.001) and GAF (P < 0.05) scores. Other differences between both schizophrenic patient groups were found for measures of clinical deterioration, employment status and full symptomatic remission rates at 1 year. Although no consistent difference was found between recent and long-term patient groups for hospitalization parameters, the difference in length of full hospitalization days was statistically significantly different (P < 0.01) between e-STAR 'Early' and 'Late' patient groups at both 12- and 24-month endpoints: the mean change from baseline was significantly greater for e-STAR 'Early' at 12 months, but greater for e-STAR 'Late' at 24 months. CONCLUSIONS: The findings of the post hoc analyses support the significance of pharmacological interventions, such as long-acting risperidone, in addressing discontinuity issues, especially in recently diagnosed patients.

Attitudes towards the administration of long-acting antipsychotics: a survey of physicians and nurses.

BACKGROUND: Discontinuation of antipsychotic treatment for schizophrenia can interrupt improvement and exacerbate the illness. Reasons for discontinuing treatment are multifactorial and include adherence, efficacy and tolerability issues. Poor adherence may be addressed through non-pharmacological approaches as well as through pharmacological ones, ie ensured delivery of medication, such as that achieved with long-acting injectable (LAI) antipsychotics. However, attitudes of healthcare professionals (HCPs) towards LAI antipsychotics may influence their prescribing decisions and may influence medication choices offered to patients. We therefore conducted a survey to investigate factors driving LAI use as well as physician and nurse attitudes to LAI antipsychotics and to different injection sites. METHODS: An independent market research agency conducted the survey of HCPs across Europe. Participants were recruited by telephone and completed the survey online. Using conjoint analyses (a multivariate statistical technique analysing preferences on the basis of ranking a limited number of attributes which are presented repetitively), attitudes to oral versus LAI medication and gluteal versus deltoid injection routes were assessed. RESULTS: A total of 891 HCPs across Europe were surveyed. Of these, 40% would choose LAI antipsychotics for first episode patients whereas 90% would select LAI antipsychotics for chronic patients with two to five psychotic episodes. Dominant elements in antipsychotic choice were low sedation but no tardive dyskinesia, no or mild pain at injection and low risk of embarrassment or impact upon therapeutic alliance. Eighty-six per cent of respondents considered that having the choice of a deltoid as well as gluteal administration site was beneficial over not having that choice. Two thirds of respondents said they agreed that medication administration via the deltoid muscle may reduce social embarrassment associated with LAI antipsychotics and most respondents (61%) believed that administration of LAI antipsychotics into the deltoid muscle as opposed to the gluteal muscle may be more respectful to the patient. CONCLUSIONS: In this survey of physicians and nurses, attitudes towards LAI antipsychotics compared with oral medication were generally positive. Respondents considered that the availability of a deltoid administration route would offer increased choice in LAI antipsychotic administration and may be perceived as more respectful and less socially embarrassing.

Multiplex Manager 1.0: a cross-platform computer program that plans and optimizes multiplex PCR.

Multiplex Manager 1.0 is a user-friendly cross-platform program that designs efficient combinations of existing genetic marker loci into multiplex polymerase chain reactions and optimizes using prior marker information. The program has the flexibility to solve two design problems: combining all markers into the smallest number of reactions, or alternatively, selecting a subset from many available markers to design an efficient and robust multiplex. Our program minimizes the number of reactions, the genetic linkage, and the difference in annealing temperature. At the same time it maximizes the spacing between markers, the heterozygosity, and the number of alleles. The final output provides easily interpreted and informative graphical representations of reactions, as well as the option of manually editing final reactions. Multiplex Manager 1.0 is freely available at www.multiplexmanager.com.