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Waldenström macroglobulinemia (WM) is a rare B-cell Non-Hodgkin Lymphoma. There are only few prospective randomized clinical trials to guide treatment recommendations and there is no international consensus on a preferred first line treatment approach. In the recently revised Dutch guideline for WM, we describe recommendations for practice based as much as possible on the known data. Here, we summarize the considerations for first-line treatment based on these Dutch guidelines. Available evidence is summarized, including efficacy and toxicity data. Combinations of Rituximab with chemotherapy, proteasome inhibition or BTK-inhibition are all valid first line treatment options. The Dutch WM working group considers Dexamethasone/Rituximab/Cylofosfamide (DRC) a suitable first-line treatment for many WM patients, given the efficacy, the relatively mild toxicity profile and the extensive experience with this regimen. However, the long-term toxicities of DRC are unclear and need further clarification. Other regimens such as R-bendamustine, R-Bortezomib-dexamethason are also effective options, however with specific toxicities. BTK-inhibitors are not a preferred option in first line for most patients in the Dutch WM guidelines because of the need for longterm treatment and toxicities. Based on patient preferences research, future clinical trials should focus on effective fixed-duration regimens with non-cytotoxic therapies that have a favorable toxicity profile. Further development of (combinations with) BCL-2 inhibititors, novel proteasome inhibitors and BTK-inhibition could be interesting. In addition T-cell-directed treatments including bispecific antibodies as a monotherapy or combined with other novel agents deserve further study in WM. [ABSTRACT FROM AUTHOR]

Summary: Contemporary diagnosed WM patients, compared to the general population, continue to experience excess mortality regardless of having survived up to 15 years post‐diagnosis. This gradual increase in excess mortality might result from the incurable nature of this disease characterized by multiple relapses throughout the disease course with limited efficacious treatment options in the released/refractory setting. [ABSTRACT FROM AUTHOR]

Summary: It is unclear how treatment advances impacted the population‐level survival of patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia (LPL/WM). Therefore, we assessed trends in first‐line therapy and relative survival (RS) among patients with LPL/WM diagnosed in the Netherlands between 1989 and 2018 (N = 6232; median age, 70 years; 61% males) using data from the nationwide Netherlands Cancer Registry. Patients were grouped into three age groups (<65, 66–75 and >75 years) and four calendar periods. Overall, treatment with anti‐neoplastic agents within 1 year post‐diagnosis gradually decreased over time, following a broader application of an initial watch‐and‐wait approach. Approximately 40% of patients received anti‐neoplastic therapy during 2011–2018. Furthermore, use of chemotherapy alone decreased over time, following an increased application of chemoimmunotherapy. Detailed data among 1596 patients diagnosed during 2014–2018 revealed that dexamethasone‐rituximab‐cyclophosphamide was the most frequently applied regimen; its use increased from 14% to 39% between 2014 and 2018. The 5‐year RS increased significantly over time, particularly since the introduction of rituximab in the early–mid 2000s. The 5‐year RS during 1989–1995 was 75%, 65%, and 46% across the age groups compared to 93%, 85%, and 79% during 2011–2018. However, the survival improvement was less pronounced after 2011. Collectively, the impressive survival improvement may be accounted for by broader application of rituximab‐containing therapy. The lack of survival improvement in the post‐rituximab era warrants studies across multiple lines of therapy to further improve survival in LPL/WM. [ABSTRACT FROM AUTHOR]

Paraproteinaemic neuropathies are a heterogeneous group of disorders most frequently associated with IgM monoclonal gammopathies including Waldenström macroglobulinaemia ( WM). Their consequences are significant for affected patients, and their management challenging for their physicians. The variability in clinical presentation and time course hamper classification and management. The indications for invasive investigations such as cerebrospinal fluid analysis, nerve conduction tests and sensory nerve biopsies are unclear, and the optimum way to measure clinical response to treatment unknown. When to intervene and and how to treat, also present challenges to physicians. As part of its latest deliberations at the International Workshops on WM ( IWWM) in London, UK (August 2014), the IWWM8 panel have proposed a consensus approach to the diagnosis and management of peripheral neuropathies associated with IgM monoclonal gammopathies, including WM. Importantly, a consensus regarding the use of clinical outcome measures and recommended models of care for this group of patients is discussed, as well as appropriate treatment interventions. [ABSTRACT FROM AUTHOR]

Abstract: Therapeutic monoclonal antibodies (MoAbs) have been the major breakthrough in the treatment of both indolent and aggressive B-cell non-Hodgkin’s lymphoma (NHL), and have become standard of care for these diseases. However, patients may not respond to antibody therapy, or resistance can develop. Radioimmunotherapy (RIT) makes use of continuous low dose radiation emitted by radioisotopes targeted directly to the lymphoma cells. Both the 131I-labeled murine CD20 MoAb tositumomab (Bexxar®) and 90Y-labeled ibritumomab-tiuxetan (Zevalin®) have been shown to be more effective than unlabeled MoAbs in terms of overall and complete response rates in follicular lymphoma (FL) patients, and both agents have a high response rate even in rituximab-resistant patients. Long-term responses, especially in complete responders, have been described in up to one third of the patients. In FL patients consolidation with 90Y-labeled ibritumomab-tiuxetan after first line treatment with chemotherapy has been shown to result in a high rate of conversion of partial to complete remissions, leading to a significant improvement in progression-free survival. Current (mostly phase II) clinical trials are investigating the role of RIT in induction or consolidation therapy after immunochemotherapy, and are incorporating RIT in high dose chemotherapy regimens followed by autologous stem cell rescue. However, phase III data are important to define the place of RIT in the treatment algorithm of patients with FL. [Copyright &y& Elsevier]

Background: The use of high-dose chemotherapy combined with autologous stem cell transplantation has improved the outcome of hematologic malignancies. Nevertheless, this treatment can cause persistent fatigue and a reduced global quality of life, role and physical function. Physical exercise interventions may be beneficial for physical fitness, fatigue and quality of life. However, the trials conducted so far to test the effects of physical exercise interventions in this group of patients were of poor to moderate methodological quality and economic evaluations are lacking. Hence there is need for a rigorous, appropriately controlled assessment of the effectiveness of exercise programs in these patients. The aims of the present study are (1) to determine the effectiveness of an individualized high intensity strength and interval training program with respect to physiological and psychological health status in patients with multiple myeloma or (non-)Hodgkin's lymphoma who have recently undergone high dose chemotherapy followed by autologous stem cell transplantation; and (2) to evaluate the cost-effectiveness of this program. Methods: A multicenter, prospective, single blind randomized controlled trial will be performed. We aim to recruit 120 patients within an inclusion period of 2 years at 7 hospitals in the Netherlands. The patients will be randomly assigned to one of two groups: (1) intervention plus usual care; or (2) usual care. The intervention consists of an 18-week individualized supervised high-intensity exercise program and counselling. The primary outcomes (cardiorespiratory fitness, muscle strength and fatigue) and secondary outcomes are assessed at baseline, at completion of the intervention and at 12 months follow-up. [ABSTRACT FROM AUTHOR]

Discusses the proceedings of the Second International Lunenburg Workshop on prognostic factors in follicular lymphoma and diffuse large-cell lymphoma at the Lunenburg Estate in Langbroek, the Netherlands on May 19 and 20, 2003. Problems related to the International Prognostic Index; Prognostic factors in follicular non-Hodgkin's lymphoma; Prognostic factors in diffuse large-B-cell lymphoma.

Simple Summary: CAR T-cell therapy became standard of care for patients with relapsed or refractory large B-cell lymphoma. However, their administration can be accompanied by toxicities, such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. It is important to identify patients at risk for these toxicities in order to start an early intervention in high-risk patients and guide outpatient CAR T-cell treatment. As a consequence, several easy-to-use risk scores including the EASIX and its derivatives were developed. However, in the available studies, disparities existed among the used endpoints and cutoff values, hampering the utility of these tools in practice. This study aims to validate these EASIX scores in a population-based cohort. This can be used to select the best predictive model and to further guide optimization of the proposed risk scores. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can hamper the clinical benefit of CAR T-cell therapy in patients with relapsed/refractory large B-cell lymphoma (r/r LBCL). To assess the risk of CRS and ICANS, the endothelial activation and stress index (EASIX), the modified EASIX (m-EASIX), simplified EASIX (s-EASIX), and EASIX with CRP/ferritin (EASIX-F(C)) were proposed. This study validates these scores in a consecutive population-based cohort. Patients with r/r LBCL treated with axicabtagene ciloleucel were included (n = 154). EASIX scores were calculated at baseline, before lymphodepletion (pre-LD) and at CAR T-cell infusion. The EASIX and the s-EASIX at pre-LD were significantly associated with ICANS grade ≥ 2 (both p = 0.04), and the EASIX approached statistical significance at infusion (p = 0.05). However, the predictive performance was moderate, with area under the curves of 0.61–0.62. Validation of the EASIX-FC revealed that patients in the intermediate risk group had an increased risk of ICANS grade ≥ 2 compared to low-risk patients. No significant associations between EASIX scores and CRS/ICANS grade ≥ 3 were found. The (m-/s-) EASIX can be used to assess the risk of ICANS grade ≥ 2 in patients treated with CAR T-cell therapy. However, due to the moderate performance of the scores, further optimization needs to be performed before broad implementation as a clinical tool, directing early intervention and guiding outpatient CAR T-cell treatment. [ABSTRACT FROM AUTHOR]

The authors discuss a study by G. C. Caponetti and colleagues regarding the significance of a single regulator gene MYC aberration, and rearrangements of BLC2 and BLC6 proteins in diffuse large B-cell lymphoma (DLBCL). Topics include a meta-analysis on the effect the rearrangement of MYC on DLBCL's prognosis, the use of immunochemotherapy, and the gene regulation for cell proliferation and metabolism.

Aims: Subclassification of large B cell lymphoma (LBCL) is challenging due to the overlap in histopathological, immunophenotypical and genetic data. In particular, the criteria to separate diffuse large B cell lymphoma (DLBCL) and high‐grade B cell lymphoma (HGBL) are difficult to apply in practice. The Lunenburg Lymphoma Biomarker Consortium previously reported a cohort of over 5000 LBCL that included fluorescence in‐situ hybridisation (FISH) data. This cohort contained 209 cases with MYC rearrangement that were available for a validation study by a panel of eight expert haematopathologists of how various histopathological features are used. Methods and results: Digital whole slide images of haematoxylin and eosin‐stained sections allowed the pathologists to visually score cases independently as well as participate in virtual joint review conferences. Standardised consensus guidelines were formulated for scoring histopathological features and included overall architecture/growth pattern, presence or absence of a starry‐sky pattern, cell size, nuclear pleomorphism, nucleolar prominence and a range of cytological characteristics. Despite the use of consensus guidelines, the results show a high degree of discordance among the eight expert pathologists. Approximately 50% of the cases lacked a majority score, and this discordance spanned all six histopathological features. Moreover, none of the histological variables aided in prediction of MYC single versus double/triple‐hit or immunoglobulin‐partner FISH‐based designations or clinical outcome measures. Conclusions: Our findings indicate that there are no specific conventional morphological parameters that help to subclassify MYC‐rearranged LBCL or select cases for FISH analysis, and that incorporation of FISH data is essential for accurate classification and prognostication. [ABSTRACT FROM AUTHOR]

Introduction: Treatment options for Waldenström's Macroglobulinemia (WM) have expanded rapidly in the last decades. However, there is no consensus on a preferred treatment. Therefore, patient preferences become increasingly important in making individualized treatment plans. Still, WM patients' priorities and perspectives regarding their treatment options are unknown. We evaluated treatment preferences of WM patients using a discrete choice experiment (DCE). Methods: A mixed‐method approach was utilized for identification and selection of attributes/levels. The DCE questionnaire included five attributes: type of agent (targeted versus chemotherapy); frequency and route of administration; 5‐year progression‐free survival (PFS); adverse events; and risk of secondary malignancies. An orthogonal design and a mixed logit panel data model were used to construct choice tasks and assess patient preferences, respectively. Results: Three hundred thirty WM patients participated in the project. In total, 214 (65%) complete questionnaires were included for data analysis. The 5‐year PFS, followed by risk of secondary malignancies were the most important attributes for making treatment choices. Regarding side effects, patients chose to avoid neuropathy the most compared to nausea/vomiting and extreme fatigue. Patients preferred a fixed‐duration treatment with IV/SC administration at the hospital over a continuous daily oral regimen at home. Conclusion: These are the first systematic data obtained on WM patient preferences for treatment. The results may help discussions with individual patients about their treatment choices. Also, these data can help design clinical trials in WM and inform health‐care decision‐making regarding outcomes that are most relevant to patients. [ABSTRACT FROM AUTHOR]

Background: HIV testing among patients with malignant lymphoma (PWML) is variably implemented. We evaluated HIV testing among PWML, and mapped factors influencing hematologists' testing behavior. Materials: We conducted a mixed-methods study assessing HIV testing among PWML, factors influencing HIV testing and opportunities for improvement in five hospitals in the region of Amsterdam, the Netherlands. The proportion of PWML tested for HIV within 3 months before or after lymphoma diagnosis and percentage positive were assessed from January 2015 through June 2020. Questionnaires on intention, behavior and psychosocial determinants for HIV testing were conducted among hematologists. Through twelve semi-structured interviews among hematologists and authors of hematology guidelines, we further explored influencing factors and opportunities for improvement. Findings: Overall, 1,612 PWML were included for analysis, including 976 patients newly diagnosed and 636 patients who were referred or with progressive/relapsed lymphoma. Seventy percent (678/976) of patients newly diagnosed and 54% (343/636) of patients with known lymphoma were tested for HIV. Overall, 7/1,021 (0.7%) PWML tested HIV positive, exceeding the 0.1% cost-effectiveness threshold. Questionnaires were completed by 40/77 invited hematologists, and 85% reported intention to test PWML for HIV. In the interviews, hematologists reported varying HIV testing strategies, including testing all PWML or only when lymphoma treatment is required. Recommendations for improved HIV testing included guideline adaptations, providing electronic reminders and monitoring and increasing awareness. Conclusions: Missed opportunities for HIV testing among PWML occurred and HIV test strategies varied among hematologists. Efforts to improve HIV testing among PWML should include a combination of approaches. [ABSTRACT FROM AUTHOR]

Background: The use of high-dose chemotherapy combined with autologous stem cell transplantation has improved the outcome of hematologic malignancies. Nevertheless, this treatment can cause persistent fatigue and a reduced global quality of life, role and physical function. Physical exercise interventions may be beneficial for physical fitness, fatigue and quality of life. However, the trials conducted so far to test the effects of physical exercise interventions in this group of patients were of poor to moderate methodological quality and economic evaluations are lacking. Hence there is need for a rigorous, appropriately controlled assessment of the effectiveness of exercise programs in these patients. The aims of the present study are (1) to determine the effectiveness of an individualized high intensity strength and interval training program with respect to physiological and psychological health status in patients with multiple myeloma or (non-)Hodgkin's lymphoma who have recently undergone high dose chemotherapy followed by autologous stem cell transplantation; and (2) to evaluate the cost-effectiveness of this program.Methods: A multicenter, prospective, single blind randomized controlled trial will be performed. We aim to recruit 120 patients within an inclusion period of 2 years at 7 hospitals in the Netherlands. The patients will be randomly assigned to one of two groups: (1) intervention plus usual care; or (2) usual care. The intervention consists of an 18-week individualized supervised high-intensity exercise program and counselling. The primary outcomes (cardiorespiratory fitness, muscle strength and fatigue) and secondary outcomes are assessed at baseline, at completion of the intervention and at 12 months follow-up.Discussion: The strengths of this study include the solid trial design with clearly defined research groups and standardized outcome measures, the inclusion of an economic evaluation and the inclusion of both resistance and endurance exercise in the intervention program.Trial Registration: This study is registered at the Netherlands Trial Register (NTR2341). [ABSTRACT FROM AUTHOR]

Purpose: System science offers a unique set of tools, including causal loop diagrams (CLDs), for stakeholders to better grasp the complexity of factors surrounding quality of life. Because the health-related quality of life (HRQoL) of cancer immunotherapy patients exists within an intricate system affected by and affecting many factors across multiple dimensions, the development of a systems-level model can provide a powerful framework to aid the understanding of this complexity. We developed a CLD for HRQoL of cancer immunotherapy patients. Methods: We first applied a literature-based approach to construct a CLD for patients following immunotherapy. We then iteratively reviewed and enhanced the CLD through interviews with subject matter experts. Results: Based on the reviewed literature and subject matter expert input, we produced a CLD representing the system surrounding cancer immunotherapy patients' HRQoL. Several feedback loops are identified that span clinical experiences, oncology teams' perceptions about immunotherapy, social support structures, and further research and development in cancer immunotherapy, in addition to other components. The CLD enables visualization of thought experiments regarding how a change anywhere in the system can ultimately worsen or improve patients' HRQoL. Conclusion: The CLD illustrates the valuable contribution of a systems perspective to quality-of-life research. This systems-based qualitative representation gives insight on strategies to inhibit harmful effects, enhance beneficial effects, and inherent tradeoffs within the system. The CLD identifies gaps in the literature and offers a communication tool for diverse stakeholders. Our research method provides an example for studying the complexities of quality of life in other health domains. [ABSTRACT FROM AUTHOR]

Introduction: In anti-myelin-associated glycoprotein IgM paraprotein-related peripheral neuropathy (anti-MAG PN), there is a lack of reliable biomarkers to select patients eligible for therapy and for evaluating treatment effects, both in routine practice and in clinical trials. Neurofilament light chain (NfL) and contactin-1 (CNTN1) can serve as markers of axonal and paranodal damage. Complement activation is involved in the pathogenesis in anti-MAG PN. We, therefore, hypothesized that serum NfL, CNTN1, C3b/c and C4b/c may function as biomarkers of disease activity in anti-MAG PN. Methods: In this prospective cohort study, we included 24 treatment-naïve patients with anti-MAG PN (mean age 69 years, 57% male) that had IgM paraproteinemia, a high IgM MAG-antibody, and clinical diagnosis of anti-MAG PN by a neurologist specialized in peripheral nerve disorders. We measured serum NfL, CNTN1, C3b/c and C4b/c, reference values were based on healthy controls. As controls, 10 treatment-naïve patients with IgM Monoclonal gammopathy of undetermined significance (MGUS) or Waldenström's Macroglobulinemia (mean age 69 years, 60% male) without signs of neuropathy were included (non-PN). Results: NfL, CNTN1 levels in serum were mostly normal in anti-MAG PN patients and comparable to non-PN patients. C3b/c and C4b/c levels were normal in anti-MAG PN patients. Conclusion: Our results do not support serum NfL, CNTN1, and C3b/c and C4b/c as potential biomarkers in anti-MAG PN, although we cannot exclude that subgroups or subtle abnormalities could be found in a much larger cohort with longitudinal follow-up. [ABSTRACT FROM AUTHOR]

Since WM PB blood T-cells appear to resemble T-cells from HD, we hypothesized this could be due to the lack of interaction with the WM tumor cells that mainly reside in the BM. Waldenström's macroglobulinemia (WM) is an incurable low-grade B-cell non-Hodgkin lymphoma (B-NHL) characterized by bone marrow (BM) infiltration with lymphoplasmacytic cells, and the presence of an IgM paraproteinemia. WM resembles chronic lymphocytic leukemia (CLL) with regard to various biologic and clinical characteristics; both B cell malignancies have an indolent course with low proliferation rates, and a comparable gene expression profile similar to that of peripheral blood (PB) resting B-cells closely related to memory B cells [[3]]. Lymphocyte analysis in PB samples from WM patients (n = 26) HDs (n = 21) and CLL patients (n = 17) and in BM samples from WM patients (n = 10) and HD (n = 10) by flow cytometry. [Extracted from the article]

Discrimination between Waldenström macroglobulinemia (WM) and marginal zone lymphoma (MZL) of the bone marrow (BM) can be difficult due to overlap in clinical, histopathologic, and immunophenotypic characteristics. We determined which characteristics can aid in the differential diagnosis of 'gray zone' cases. We compared clinical, histopathologic, immunophenotypic, and molecular features of 222 WM and 65 MZL patients. LASSO regression was employed for variable selection. The most distinguishing clinical features of WM compared to MZL were the presence of the B-symptom weight loss and IgM paraprotein. Histopathological findings were plasmacytoid differentiation, monoclonal plasma cells, and increased mast cells in the BM. Regarding flow cytometry, only CD10 and CD38 were distinguishing markers. Finally, as the expected presence of the MYD88L265P mutation showed to be of great value in the distinction between WM and MZL. Despite the great overlap, WM can often be distinguished from MZL by using a combination of characteristics. These characteristics should be weighed in complex, 'gray zone' cases. [ABSTRACT FROM AUTHOR]

Simple Summary: This review summarizes gene-expression profiling insights into the background and origination of diffuse large B-cell lymphomas (DLBCL). To further unravel the molecular biology of these lymphomas, a consortium panel called BLYM-777 was designed including genes important for subtype classifications, genetic pathways, tumor-microenvironment, immune response and resistance to targeted therapies. This review proposes to combine this transcriptomic method with genomics, proteomics, and patient characteristics to facilitate diagnostic classification, prognostication, and the development of new targeted therapeutic strategies in DLBCL. Gene-expression profiling (GEP) is used to study the molecular biology of lymphomas. Here, advancing insights from GEP studies in diffuse large B-cell lymphoma (DLBCL) lymphomagenesis are discussed. GEP studies elucidated subtypes based on cell-of-origin principles and profoundly changed the biological understanding of DLBCL with clinical relevance. Studies integrating GEP and next-generation DNA sequencing defined different molecular subtypes of DLBCL entities originating at specific anatomical localizations. With the emergence of high-throughput technologies, the tumor microenvironment (TME) has been recognized as a critical component in DLBCL pathogenesis. TME studies have characterized so-called "lymphoma microenvironments" and "ecotypes". Despite gained insights, unexplained chemo-refractoriness in DLBCL remains. To further elucidate the complex biology of DLBCL, we propose a novel targeted GEP consortium panel, called BLYM-777. This knowledge-based biology-driven panel includes probes for 777 genes, covering many aspects regarding B-cell lymphomagenesis (f.e., MYC signature, TME, immune surveillance and resistance to CAR T-cell therapy). Regarding lymphomagenesis, upcoming DLBCL studies need to incorporate genomic and transcriptomic approaches with proteomic methods and correlate these multi-omics data with patient characteristics of well-defined and homogeneous cohorts. This multilayered methodology potentially enhances diagnostic classification of DLBCL subtypes, prognostication, and the development of novel targeted therapeutic strategies. [ABSTRACT FROM AUTHOR]

This study compared overall survival (OS), progression-free survival (PFS), complete response rate (CRR), and overall response rate (ORR) of tisagenlecleucel (tisa-cel) and lisocabtagene maraleucel (liso-cel) in relapsed or refractory large B-cell lymphomas (r/r LBCL). Using matching-adjusted indirect comparison (MAIC), individual patient-level data from JULIET (tisa-cel) were weighted to match the patient population in TRANSCEND (liso-cel). The main analysis compared infused JULIET patients (N = 106) with the TRANSCEND efficacy-evaluable set (EES) (N = 256 [infused]). After adjustment, OS, PFS, and the CRR were comparable between tisa-cel and liso-cel EES patients. The estimated adjusted 2-year OS, 2-year PFS, ORR, and CRR were 45.6, 38.2, 62.9, and 47.7%, respectively, for tisa-cel vs. 43.8, 42.1, 72.7, and 53.1% for liso-cel. A scenario analysis compared JULIET patients to the TRANSCEND primary analysis set (PAS) (N = 133). ORR was significantly higher in the TRANSCEND PAS compared with matched JULIET patients, but no significant differences in CRR were observed. [ABSTRACT FROM AUTHOR]

Background: This study aimed to evaluate the reliability and validity of two self-report physical activity (PA) questionnaires - the AQuAA (Activity Questionnaire for Adults and Adolescents) and PASE (Physical Activity Scale for the Elderly) - in cancer patients. Methods: Test-retest reliability was determined by administering the questionnaires twice within 5 days. Intraclass correlation coefficient (ICC), standard error of measurement (SEM) and smallest detectable difference (SDD) were calculated. Construct validity was determined by comparing the questionnaire results with ActiGraph accelerometer scores using Spearman correlation coefficients (rs) and ICCs. Content validity was examined using the Three-Step Test-Interview (TSTI). Results: Reliability for the AQuAA scores were fair to excellent (ICC = 0.57 to 0.78). Reliability for the PASE scores ranged from good to excellent (ICC = 0.67 to 0.90). Correlations between the ActiGraph and the AQuAA and the PASE were low (rs = 0.05 and 0.16 respectively, and ICC = -0.001 to 0.44). The TSTI showed that participants experienced difficulties with the examples provided with the questions, the perceptions of intensity level of PA, and with recalling the time spent on PA. Conclusions: Both questionnaires showed good to excellent test-retest reliability for most scores. Construct validity of both questionnaires was low, as indicated by the low correlations with the ActiGraph. Except for a few difficulties that participants perceived when filling out the questionnaires, the content validity of both questionnaires was good. [ABSTRACT FROM AUTHOR]

Background: In the primary analysis of the pivotal JULIET trial of tisagenlecleucel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, the best overall response rate was 52% and the complete response rate was 40% in 93 evaluable adult patients with relapsed or refractory aggressive B-cell lymphomas. We aimed to do a long-term follow-up analysis of the clinical outcomes and correlative analyses of activity and safety in the full adult cohort.Methods: In this multicentre, open-label, single-arm, phase 2 trial (JULIET) done at 27 treatment sites in ten countries (Australia, Austria, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, and the USA), adult patients (≥18 years) with histologically confirmed relapsed or refractory large B-cell lymphomas who were ineligible for, did not consent to, or had disease progression after autologous haematopoietic stem-cell transplantation, with an Eastern Cooperative Oncology Group performance status of 0-1 at screening, were enrolled. Patients received a single intravenous infusion of tisagenlecleucel (target dose 5 × 108 viable transduced CAR T cells). The primary endpoint was overall response rate (ie, the proportion of patients with a best overall disease response of a complete response or partial response using the Lugano classification, as assessed by an independent review committee) at any time post-infusion and was analysed in all patients who received tisagenlecleucel (the full analysis set). Safety was analysed in all patients who received tisagenlecleucel. JULIET is registered with ClinialTrials.gov, NCT02445248, and is ongoing.Findings: Between July 29, 2015, and Nov 2, 2017, 167 patients were enrolled. As of Feb 20, 2020, 115 patients had received tisagenlecleucel infusion and were included in the full analysis set. At a median follow-up of 40·3 months (IQR 37·8-43·8), the overall response rate was 53·0% (95% CI 43·5-62·4; 61 of 115 patients), with 45 (39%) patients having a complete response as their best overall response. The most common grade 3-4 adverse events were anaemia (45 [39%]), decreased neutrophil count (39 [34%]), decreased white blood cell count (37 [32%]), decreased platelet count (32 [28%]), cytokine release syndrome (26 [23%]), neutropenia (23 [20%]), febrile neutropenia (19 [17%]), hypophosphataemia (15 [13%]), and thrombocytopenia (14 [12%]). The most common treatment-related serious adverse events were cytokine release syndrome (31 [27%]), febrile neutropenia (seven [6%]), pyrexia (six [5%]), pancytopenia (three [3%]), and pneumonia (three [3%]). No treatment-related deaths were reported.Interpretation: Tisagenlecleucel shows durable activity and manageable safety profiles in adult patients with relapsed or refractory aggressive B-cell lymphomas. For patients with large B-cell lymphomas that are refractory to chemoimmunotherapy or relapsing after second-line therapies, tisagenlecleucel compares favourably with respect to risk-benefit relative to conventional therapeutic approaches (eg, salvage chemotherapy).Funding: Novartis Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Summary: ZUMA‐1 (NCT02348216) examined the safety and efficacy of axicabtagene ciloleucel (axi‐cel), an autologous CD19‐directed chimaeric antigen receptor (CAR)‐T cell therapy, in refractory large B‐cell lymphoma. To reduce treatment‐related toxicity, several exploratory safety management cohorts were added to ZUMA‐1. Specifically, cohort 6 investigated management of cytokine release syndrome (CRS) and neurologic events (NEs) with prophylactic corticosteroids and earlier corticosteroid and tocilizumab intervention. CRS and NE incidence and severity were primary end‐points. Following leukapheresis, patients could receive optional bridging therapy per investigator discretion. All patients received conditioning chemotherapy (days −5 through −3), 2 × 106 CAR‐T cells/kg (day 0) and once‐daily oral dexamethasone [10 mg, day 0 (before axi‐cel) through day 2]. Forty patients received axi‐cel. CRS occurred in 80% of patients (all grade ≤2). Any grade and grade 3 or higher NEs occurred in 58% and 13% of patients respectively. Sixty‐eight per cent of patients did not experience CRS or NEs within 72 h of axi‐cel. With a median follow‐up of 8·9 months, objective and complete response rates were 95% and 80% respectively. Overall, prophylactic corticosteroids and earlier corticosteroid and/or tocilizumab intervention resulted in no grade 3 or higher CRS, a low rate of grade 3 or higher NEs and high response rates in this study population. [ABSTRACT FROM AUTHOR]

Background: The survival and proliferation of multiple myeloma (MM) cells in the bone marrow (BM) critically depend on interaction with stromal cells expressing the chemokine CXCL12. CXCL12 regulates the homing to the BM niche by mediating the transendothelial migration and adhesion/retention of the MM cells. The gamma isoform of CXCL12 (CXCL12γ) has been reported to be highly expressed in mouse BM and to show enhanced biological activity compared to the 'common' CXCL12α isoform, mediated by its unique extended C-terminal domain, which binds heparan sulfate proteoglycans (HSPGs) with an extraordinary high affinity. Here, we investigated the expression of CXCL12γ in human BM and studied its functional role in the interaction of MM cells with BM stromal cells (BMSCs). Methods: We assessed CXCL12γ mRNA and protein expression by human BMSCs using qPCR, flow cytometry, and immunohistochemistry. CRISPR-Cas9 was employed to delete CXCL12γ and the heparan sulfate (HS) co-polymerase EXT1 in BMSCs. To study the functional roles of BMSC-derived CXCL12γ and HSPGs in the interaction of MM cells with BMSCs cells, MM cell lines and primary MM cells were co-cultured with BMSCs. Results: We observed that CXCL12γ is expressed in situ by reticular stromal cells in both normal and MM BM, as well as by primary BMSC isolates and BMSC lines. Importantly, upon secretion, CXCL12γ, unlike the CXCL12α isoform, was retained on the surface of BMSCs. This membrane retention of CXCL12γ is HSPG mediated, since it was completely annulated by CRISPR-Cas9-mediated deletion of the HS co-polymerase EXT1. CXCL12γ expressed by BMSCs and membrane-retained by HSPGs supported robust adhesion of MM cells to the BMSCs. Specific genetic deletion of either CXCL12γ or EXT1 significantly attenuated the ability of BMSCs to support MM cell adhesion and, in addition, impaired their capacity to protect MM cells from bortezomib-induced cell death. Conclusions: We show that CXCL12γ is expressed by human BMSCs and upon secretion is retained on their cell surface by HSPGs. The membrane-bound CXCL12γ controls adhesion of MM cells to the stromal niche and mediates drug resistance. These findings designate CXCL12γ and associated HSPGs as partners in mediating MM–niche interaction and as potential therapeutic targets in MM. [ABSTRACT FROM AUTHOR]

Background: The survival and proliferation of multiple myeloma (MM) cells in the bone marrow (BM) critically depend on interaction with stromal cells expressing the chemokine CXCL12. CXCL12 regulates the homing to the BM niche by mediating the transendothelial migration and adhesion/retention of the MM cells. The gamma isoform of CXCL12 (CXCL12γ) has been reported to be highly expressed in mouse BM and to show enhanced biological activity compared to the 'common' CXCL12α isoform, mediated by its unique extended C-terminal domain, which binds heparan sulfate proteoglycans (HSPGs) with an extraordinary high affinity. Here, we investigated the expression of CXCL12γ in human BM and studied its functional role in the interaction of MM cells with BM stromal cells (BMSCs). Methods: We assessed CXCL12γ mRNA and protein expression by human BMSCs using qPCR, flow cytometry, and immunohistochemistry. CRISPR-Cas9 was employed to delete CXCL12γ and the heparan sulfate (HS) co-polymerase EXT1 in BMSCs. To study the functional roles of BMSC-derived CXCL12γ and HSPGs in the interaction of MM cells with BMSCs cells, MM cell lines and primary MM cells were co-cultured with BMSCs. Results: We observed that CXCL12γ is expressed in situ by reticular stromal cells in both normal and MM BM, as well as by primary BMSC isolates and BMSC lines. Importantly, upon secretion, CXCL12γ, unlike the CXCL12α isoform, was retained on the surface of BMSCs. This membrane retention of CXCL12γ is HSPG mediated, since it was completely annulated by CRISPR-Cas9-mediated deletion of the HS co-polymerase EXT1. CXCL12γ expressed by BMSCs and membrane-retained by HSPGs supported robust adhesion of MM cells to the BMSCs. Specific genetic deletion of either CXCL12γ or EXT1 significantly attenuated the ability of BMSCs to support MM cell adhesion and, in addition, impaired their capacity to protect MM cells from bortezomib-induced cell death. Conclusions: We show that CXCL12γ is expressed by human BMSCs and upon secretion is retained on their cell surface by HSPGs. The membrane-bound CXCL12γ controls adhesion of MM cells to the stromal niche and mediates drug resistance. These findings designate CXCL12γ and associated HSPGs as partners in mediating MM–niche interaction and as potential therapeutic targets in MM. [ABSTRACT FROM AUTHOR]

Background: The survival and proliferation of multiple myeloma (MM) cells in the bone marrow (BM) critically depend on interaction with stromal cells expressing the chemokine CXCL12. CXCL12 regulates the homing to the BM niche by mediating the transendothelial migration and adhesion/retention of the MM cells. The gamma isoform of CXCL12 (CXCL12γ) has been reported to be highly expressed in mouse BM and to show enhanced biological activity compared to the 'common' CXCL12α isoform, mediated by its unique extended C-terminal domain, which binds heparan sulfate proteoglycans (HSPGs) with an extraordinary high affinity. Here, we investigated the expression of CXCL12γ in human BM and studied its functional role in the interaction of MM cells with BM stromal cells (BMSCs). Methods: We assessed CXCL12γ mRNA and protein expression by human BMSCs using qPCR, flow cytometry, and immunohistochemistry. CRISPR-Cas9 was employed to delete CXCL12γ and the heparan sulfate (HS) co-polymerase EXT1 in BMSCs. To study the functional roles of BMSC-derived CXCL12γ and HSPGs in the interaction of MM cells with BMSCs cells, MM cell lines and primary MM cells were co-cultured with BMSCs. Results: We observed that CXCL12γ is expressed in situ by reticular stromal cells in both normal and MM BM, as well as by primary BMSC isolates and BMSC lines. Importantly, upon secretion, CXCL12γ, unlike the CXCL12α isoform, was retained on the surface of BMSCs. This membrane retention of CXCL12γ is HSPG mediated, since it was completely annulated by CRISPR-Cas9-mediated deletion of the HS co-polymerase EXT1. CXCL12γ expressed by BMSCs and membrane-retained by HSPGs supported robust adhesion of MM cells to the BMSCs. Specific genetic deletion of either CXCL12γ or EXT1 significantly attenuated the ability of BMSCs to support MM cell adhesion and, in addition, impaired their capacity to protect MM cells from bortezomib-induced cell death. Conclusions: We show that CXCL12γ is expressed by human BMSCs and upon secretion is retained on their cell surface by HSPGs. The membrane-bound CXCL12γ controls adhesion of MM cells to the stromal niche and mediates drug resistance. These findings designate CXCL12γ and associated HSPGs as partners in mediating MM–niche interaction and as potential therapeutic targets in MM. [ABSTRACT FROM AUTHOR]

Purpose: The level of daily physical activity in patients with cancer is frequently assessed by questionnaires, such as the Physical Activity Scale for the Elderly (PASE). Objective assessments, with for example accelerometers, may be a good alternative. The aim of this study was to investigate the agreement between the PASE questionnaire and accelerometer-assessed physical activity in a large group of patients with different types of cancer.Methods: Baseline accelerometer and PASE questionnaire data of 403 participants from the REACT (Resistance and Endurance Exercise After Chemotherapy, n = 227), the EXIST (Exercise Intervention After Stem-Cell Transplantation, n = 74), and NET-QUBIC (NEtherlands QUality of Life And Biomedical Cohort Studies In Cancer, n = 102) studies were available for the current analyses. Physical activity was assessed by the PASE questionnaire (total score) and accelerometers (total minutes per day > 100 counts). Linear mixed models regression analysis was used to assess the agreement between the PASE questionnaire and accelerometer-assessed physical activity.Results: The mean (SD) PASE score was 95.9 (75.1) points and mean (SD) time in physical activity measured with the accelerometer was 256.6 (78.8) min per day. The agreement between the PASE score and the accelerometer data was significant, but poor (standardized regression coefficient (B) = 0.36, 95%CI = 0.27; 0.44, p < 0.01).Conclusion: Agreement between the PASE questionnaire and accelerometer-assessed physical activity was poor. The poor agreement indicates that they measure different physical activity constructs and cannot be used interchangeably to assess the level of daily physical activity in patients with cancer. [ABSTRACT FROM AUTHOR]

Summary: In this nationwide, population‐based study, we assessed trends in primary treatment and survival among 687 patients with nodular lymphocyte‐predominant Hodgkin lymphoma (75% males; median age, 40 years; and 74% stage‐I/II disease) diagnosed in the Netherlands between 1993–2016. There were no noteworthy changes in the application of primary therapy over time among adult patients across the different disease stages and age groups. Survival among various subgroups of adult patients was largely comparable to the expected survival of the general population. A particularly encouraging finding was that young adult patients experienced virtually no excess mortality, as compared to the general population. [ABSTRACT FROM AUTHOR]

Objectives: Tailoring medical information to cancer patients' needs is recommended, but there is little guidance on how to tailor, and limited research exists about its effects. Tailoring to the amount of preferred information may be easily implementable in clinic and is tested here.Methods: A video-vignette experiment was used to systematically vary video patients' information preferences (limited/extensive) and amount of provided information (additional/no additional). N = 253 cancer patients/survivors evaluated these video-recorded consultations, serving as analogue patients (APs), and completed outcome measures.Results: Tailoring information to video patients' preferences had no effect on APs' evaluation of the consultation (satisfaction, trust). Yet, there was a main effect of APs' own information preferences: Those preferring extensive information recalled (MΔ = 5.8%) and recognized (MΔ = 3.5%) more information than those preferring limited information. Moreover, information provision mattered among APs who preferred limited information: They recognized even less if provided with extensive information.Conclusions: Tailoring to the amount of video patient's information preferences did not affect APs' evaluation of the consultation (satisfaction, trust), while APs' personal information preferences determined their recall and recognition of medical information.Practice Implications: Information preferences should be assessed and tailored to in clinical practice. Overwhelming patients/survivors, who prefer limited information, should be prevented. [ABSTRACT FROM AUTHOR]

Objectives: Patient recall of medical information is usually poor. Healthcare providers can employ affect-oriented (i.e., showing care) or cognition-oriented communication styles (i.e., structuring information) to enhance recall, but research evidence is limited especially among clinical and/or older patient populations. This video-vignette study manipulated provider caring and information structuring to examine effects on recall and trust among cancer patients/survivors.Methods: In an online survey, 148 participants (Mage = 62) were randomized to one of four video conditions in a two (standard communication vs. enhanced caring) by two (standard vs. enhanced structuring) design, and completed measures of active recall, recognition, and trust.Results: Increased caring or structuring did not enhance active recall or recognition, instead both were higher among younger, female, or highly educated participants. The caring condition induced higher perceived trust in the provider within the whole sample, but trust was significantly correlated with decreased recall (r = -.268) among younger participants.Conclusions: Provider caring can strengthen the patient-provider relationship by enhancing trust. Yet, increased trust may impair recall among younger patients. Structuring treatment information did not enhance recall and recognition, but additional research is needed.Practice Implications: Providers may use additional ways of structuring/organizing information to help enhance recall (e.g., written information). [ABSTRACT FROM AUTHOR]

Background The impact of haemodialysis (HD) and kidney transplantation on quality of life (QoL) is often underestimated due to a lack of comparative studies with other patient groups. Methods We conducted a cross-sectional cohort study in 168 patients including HD patients, kidney transplant recipients (KTR), patients with a haematological malignancy either receiving chemotherapy or in remission and healthy controls. All participants completed the 36-item short form survey of health-related quality of life, the Checklist Individual Strength and the Hospital Anxiety and Depression Scale questionnaire. Results HD patients and haematological patients undergoing chemotherapy were more frequently severely fatigued (53.3% and 50% of cases) compared with KTR (33.3%), haematological patients in remission (23.3%) and healthy controls (12.1%, P < 0.001). There were no significant differences in anxiety rates. HD patients and haematological patients undergoing chemotherapy were most likely to be depressed (33.3% and 25%), compared with 16.7% of KTR, 20% of haematological patients in remission and 8.6% of healthy controls (P = 0.066). KTR reported the largest positive health change (+27%, P < 0.001), but still had a lower overall QoL than healthy controls, comparable to haematological patients in remission. HD and chemotherapy patients reported the lowest QoL scores. Conclusions Fatigue and depression are common in HD patients, resulting in a low QoL, comparable to haematological patients receiving chemotherapy. KTR do better, with scores similar to patients with a haematological malignancy in remission, but still have a lower QoL than healthy controls. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is characterized by the expansion of malignant plasma cells in the bone marrow (BM). Most MMs display aberrant Wnt/β-catenin signaling, which drives proliferation; however, they lack oncogenic Wnt pathway mutations, suggesting activation by autocrine Wnt ligands and/or paracrine Wnts from the BM microenvironment. Expression of the heparan sulfate (HS) proteoglycan syndecan-1 is a hallmark of MM. Syndecan-1 is a critical player in the complex reciprocal interaction between MM cells and their BM niche, mediating growth factor/cytokine binding and signaling by its HS chains. Here, by means of CRISPR/Cas9-mediated knockout and doxycycline-inducible short hairpin RNA-mediated knockdown of EXT1, a critical enzyme for HS polymerization, we demonstrate that the HS chains decorating syndecan-1 mediate aberrant Wnt pathway activation in MM. HS-deficient MM cells exhibited strongly decreased autocrine Wnt/β-catenin pathway activity and reduced Wnt pathway-dependent proliferation. In addition, we demonstrate that Wnts bind to the HS side chains of syndecan-1 and that this binding contributes to paracrine Wnt pathway activation through the Wnt receptor Frizzled (Fzd). Furthermore, in an HS-dependent fashion, syndecan-1 also binds osteoblast-produced R-spondin, which represses Fzd degradation by activation of LGR4, an R-spondin receptor aberrantly expressed on MM cells. Costimulation with R-spondin and its binding to HS chains decorating syndecan-1 are indispensable for optimal stimulation of Wnt signaling in MM. Taken together, our results identify syndecan-1 as a crucial component of the Wnt signalosome in MM cells, binding Wnts and R-spondins to promote aberrant Wnt/β-catenin signaling and cell growth, and suggest HS and its biosynthetic enzymes as potential targets in the treatment of MM. [ABSTRACT FROM AUTHOR]

Background: This single blind, multicenter randomized controlled trial aimed to evaluate the effectiveness of a supervised high intensity exercise program on physical fitness and fatigue in patients with multiple myeloma or lymphoma recently treated with autologous stem cell transplantation. Methods: 109 patients were randomly assigned to the 18-week exercise intervention or the usual care control group. The primary outcomes included physical fitness (VO2peak and Wpeak determined using a cardiopulmonary exercise test; grip strength and the 30s chair stand test) and fatigue (Multidimensional Fatigue Inventory) and were assessed prior to randomization and after completion of the intervention or at similar time points for the control group. Multivariable multilevel linear regression analyses were performed to assess intervention effects. Results: Patients in the intervention group attended 86% of the prescribed exercise sessions. Of the patients in the control group, 47% reported ≥10 physiotherapy sessions, which most likely included supervised exercise, suggesting a high rate of contamination. Median improvements in physical fitness ranged between 16 and 25% in the intervention group and between 12 and 19% in the control group. Fatigue decreased in both groups. There were no significant differences between the intervention and control group. Conclusion: We found no significant beneficial effects of the supervised high intensity exercise program on physical fitness and fatigue when compared to usual care. We hypothesized that the lack of significant intervention effects may relate to suboptimal timing of intervention delivery, contamination in the control group and/or suboptimal compliance to the prescribed exercise intervention. Trial registration: Netherlands Trial Register—NTR2341. [ABSTRACT FROM AUTHOR]

The unrestrained growth of tumor cells is generally attributed to mutations in essential growth control genes, but tumor cells are also affected by, or even addicted to, signals from the microenvironment. As therapeutic targets, these extrinsic signals may be equally significant as mutated oncogenes. In multiple myeloma (MM), a plasma cell malignancy, most tumors display hallmarks of active Wnt signaling but lack activatingWnt-pathway mutations, suggesting activation by autocrine Wnt ligands and/or paracrine Wnts emanating from the bone marrow (BM) niche. Here, we report a pivotal role for the R-spondin/leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) axis in driving aberrant Wnt/ β-catenin signaling in MM. We show that LGR4 is expressed by MM plasma cells, but not by normal plasma cells or B cells. This aberrant LGR4 expression is driven by IL-6/STAT3 signaling and allows MM cells to hijack R-spondins produced by (pre)osteoblasts in the BM niche, resulting in Wnt (co)receptor stabilization and a dramatically increased sensitivity to auto- and paracrine Wnts. Our study identifies aberrant R-spondin/LGR4 signaling with consequent deregulation of Wnt (co)receptor turnover as a driver of oncogenic Wnt/ β-catenin signaling in MM cells. These results advocate targeting of the LGR4/R-spondin interaction as a therapeutic strategy in MM. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which presents a case of septic arthritis caused by coagulase-negative Staphylococci (CoNS) in a neutropenic patient.

Inhibition of B-cell receptor (BCR) signaling pathways in chronic lymphocytic leukemia (CLL) provides significant clinical benefit to patients, mainly by blocking adhesion of CLL cells in the lymph node microenvironment. The currently applied inhibitors ibrutinib and idelalisib have limited capacity however to induce cell death as monotherapy and are unlikely to eradicate the disease. Acquired resistance to therapy in CLL is often caused by mutations in the response network being targeted, both for DNA damage or BCR signaling pathways. Thus, drugs with dual targeting capacity could offer improved therapeutic value. Here, the potency of CC-115, a novel inhibitor of mammalian target of rapamycin kinase (TORK) and DNA-dependent protein kinase (DNA-PK),was evaluated in primary CLL cells in vitro and in CLL patients. Combined TORK and DNA-PK inhibition in vitro resulted in caspase-dependent cell killing irrespective of p53, ATM, NOTCH1, or SF3B1 status. Proliferation induced by CD40+ interleukin-21 stimulation was completely blocked by CC-115, and CD40-mediated resistance to fludarabine and venetoclax could be reverted by CC-115. BCR-mediated signaling was inhibited by CC-115 and also in CLL samples obtained from patients with acquired resistance to idelalisib treatment. Clinical efficacy of CC-115 was demonstrated in 8 patients with relapsed/refractory CLL/small lymphocytic lymphoma harboring ATM deletions/mutations; all but 1 patient had a decrease in lymphadenopathy, resulting in 1 IWCLL partial response (PR) and 3 PRs with lymphocytosis. In conclusion, these preclinical results, along with early promising clinical activity, suggest that CC-115 may be developed further for treatment of CLL. [ABSTRACT FROM AUTHOR]

A single-center, prospective, non-randomized clinical study was performed to examine the safety and feasibility of early discharge in patients undergoing consolidation chemotherapy for acute leukemia, or autologous stem cell transplant for lymphoma or multiple myeloma. Patients were discharged into ambulatory care the day after the last chemotherapy administration and were subsequently seen at the ambulatory care unit three times a week. One hundred and one of 224 patients were ineligible for the program, mostly because of their medical situation, the lack of a caregiver or the travel time to the hospital. The remaining 123 patients were able to spend more than 70% of the time at home. In 44% of cycles they were never readmitted. This study demonstrates the safety, feasibility and benefits of managing carefully selected patients. Patients and their caregivers felt safe and comfortable at home, and the vast majority preferred home care to in-hospital treatment. [ABSTRACT FROM AUTHOR]

In patients with chronic lymphocytic leukemia (CLL), numbers of CD8 + CD45RA +/− CD27− effector T cells are expanded. We investigated whether this expansion is also present in other B cell malignancies and the possible mechanism underlying these changes. Whereas an increase in total CD4+and CD8+ T cell numbers was found only in CLL, numbers of CD4+ and CD8+ effector T cells were significantly increased in both CLL and indolent lymphoma, but not aggressive lymphoma and myeloma. Interestingly, PD-1 expression was decreased on effector T cells and inversely correlated with effector T cell numbers, suggesting a functional role for PD-1 in regulating T cell homeostasis. In vitro experiments revealed impaired up-regulation of PD-1 upon T cell activation in the presence of malignant but also healthy B cells. Our data suggest that in CLL and indolent lymphoma, the malignant B cells affect PD-1 expression on effector T cells, resulting in an expansion of these subsets. [ABSTRACT FROM AUTHOR]

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. INSET: Continuin Medical Education online. [ABSTRACT FROM AUTHOR]

The Wnt/β-catenin pathway plays a crucial role in the pathogenesis of various human cancers. In multiple myeloma (MM), aberrant auto-and/or paracrine activation of canonical Wnt signaling promotes proliferation and dissemination, while overexpression of the Wnt inhibitor Dickkopf1 (DKK1) by MM cells contributes to osteolytic bone disease by inhibiting osteoblast differentiation. Since DKK1 itself is a target of TCF/β-catenin mediated transcription, these findings suggest that DKK1 is part of a negative feedback loop in MM and may act as a tumor suppressor. In line with this hypothesis, we show here that DKK1 expression is low or undetectable in a subset of patients with advanced MM as well as in MM cell lines. This absence of DKK1 is correlated with enhanced Wnt pathway activation, evidenced by nuclear accumulation of β-catenin, which in turn can be antagonized by restoring DKK1 expression. Analysis of the DKK1 promoter revealed CpG island methylation in several MM cell lines as well as in MM cells from patients with advanced MM. Moreover, demethylation of the DKK1 promoter restores DKK1 expression, which results in inhibition of β-catenin/TCF-mediated gene transcription in MM lines. Taken together, our data identify aberrant methylation of the DKK1 promoter as a cause of DKK1 silencing in advanced stage MM, which may play an important role in the progression of MM by unleashing Wnt signaling. [ABSTRACT FROM AUTHOR]

Abstract: Background: Although new therapeutic strategies have been developed to control Crohn''s disease, medical treatment for refractory cases is not able to prevent extensive and/or repeat surgery. Recently, several cases have been reported of successful remission induction in Crohn''s disease patients by means of hematopoietic stem cell transplantation (HSCT). Here we report our long-term (4 to 6years) outcome in three patients. Patients: Three patients (two male, one female) with active severe Crohn''s disease were planned to undergo autologous HSCT. All patients were intolerant or refractory to conventional therapies, including anti-TNFα antibodies. Patients either refused surgery or surgery was considered not to be a feasible alternative due to the extensive disease involvement of the small intestine. Methods: Peripheral blood stem cells were mobilized using a single infusion of cyclophosphamide 4g/m2, followed on day 4 by subcutaneous injections with G-CSF 5μg/kg twice daily until leukapheresis. CD34+ cells were isolated after leukapheresis by magnetic cell sorting. In two of the three patients a second round of stem cell mobilization using G-CSF only was required, either because of low yield or because of insufficient recovery after CD34 selection. Prior to transplantation, immune ablation was achieved using cyclophosphamide 50mg/kg/day (4days), antithymocyte globulin 30mg/kg/day (3days) and prednisolone 500mg (3days). Endoscopy, barium small bowel enteroclysis and MRI enterography were performed. Results: All three patients successfully completed stem cell mobilization, and two of them subsequently underwent conditioning and autologous HSCT with CD34+ cell selection. Treatment was well tolerated, with acceptable toxicity. Now, 5 and 6years post-transplantation, these patients are in remission under treatment. The third patient went into remission after mobilization and therefore she decided not to undergo conditioning and HSCT transplantation. After a successful pregnancy she relapsed two years later. Since then, she suffers from refractory Crohn''s disease for which we are now reconsidering conditioning and transplantation. Conclusion: Autologous HSCT appears to be safe and can be an alternative strategy for Crohn''s disease patients with severe and therapy resistant disease. [Copyright &y& Elsevier]

To identify which patient groups can be safely discharged early after high dose chemotherapy. Until recently, the standard of care for patients with haematological malignancies who have been treated with high dose chemotherapy has been to hospitalise them until neutrophil recovery and clinical improvement. Over the past years, a more liberal approach has resulted in a tendency to discharge patients earlier. However, currently it is unclear which clinical variables are important and which patient groups are most suitable to be discharged early. Prospective cohort study. The study group of 55 patients underwent 82 admission periods for a total of 2269 patient days, which could be classified into four categories: induction treatment, consolidation treatment and autologous or allogeneic stem cell transplantation. Different clinical variables potentially interfering with early discharge were subsequently analysed for their association with each treatment group. The median duration of admission was 27 days. The incidence of fever (82·9%) and use of intravenous antibiotics (79·3%) was high in all treatment groups. The only statistically significant differences between groups were found for performance status and mucositis. In the patient group undergoing consolidation chemotherapy for acute myeloid leukaemia, the performance status was better and mucositis was less severe. The decline in performance status and the severity of mucositis were as expected most obvious 10-14 days after the start of chemotherapy. Patients undergoing consolidation chemotherapy appear to be the most suitable candidates for early discharge, especially in the first-week postchemotherapy treatment. Early discharge can also be considered in patients with a good performance status in the autologous stem cell transplantation group, directly after transplantation. An important factor in developing an early discharge programme is a good infrastructure, both at home and in the hospital. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer-related fatigue (CRF) is one of the most frequently reported symptoms with prevalence rates of 25 to 60 percent in (non-)Hodgkin lymphoma survivors. Several (pilot) studies showed promising effects of light therapy to reduce CRF. The aim of the current study is to evaluate the short- and long-term efficacy of light therapy on CRF and associated symptoms in chronically fatigued (non-)Hodgkin lymphoma survivors. Eighty-three survivors were exposed to bright white light (intervention) and another 83 survivors were exposed to dim white light (comparison). Results showed that all participants, irrespective of light condition, reported reduced levels of fatigue after the completion of light therapy. Similar results were found for depression, sleep quality, and some aspects of quality of life. No effect was found on circadian rhythms or objectively assessed sleep. Therefore, it is important to further investigate which aspects of intervention are associated with the improvements observed after light therapy. Purpose: To evaluate the short- and long-term effects of light therapy on fatigue (primary outcome) and sleep quality, depression, anxiety, quality of life, and circadian rhythms (secondary outcomes) in survivors of (non-)Hodgkin lymphoma presenting with chronic cancer-related fatigue. Methods: We randomly assigned 166 survivors (mean survival 13 years) to a bright white light intervention (BWL) or dim white light comparison (DWL) group. Measurements were completed at baseline (T0), post-intervention (T1), at three (T2), and nine (T3) months follow-up. A mixed-effect modeling approach was used to compare linear and non-linear effects of time between groups. Results: There were no significant differences between BWL and DWL in the reduction in fatigue over time. Both BWL and DWL significantly (p < 0.001) improved fatigue levels during the intervention followed by a slight reduction in this effect during follow-up (EST0-T1 = −0.71; EST1-T3 = 0.15). Similar results were found for depression, sleep quality, and some aspects of quality of life. Light therapy had no effect on circadian rhythms. Conclusions: BWL was not superior in reducing fatigue compared to DWL in HL and DLBCL survivors. Remarkably, the total sample showed clinically relevant and persistent improvements on fatigue not commonly seen in longitudinal observational studies in these survivors. [ABSTRACT FROM AUTHOR]

Investigates whether Epstein-Barr virus (EBV) type 2 infection is highly prevalent among homosexual men. EBV type in homosexual and heterosexual men; EBV-2 infection in homosexual men in relation to sexual behavior; Prevalence of EBV-2 among persons with multiple sex partners.

A letter to the editor is presented regarding a rationale for combination therapy of ibrutinib and idelalisib in B-cell receptor (BCR)-controlled adhesion in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) .

An amendment to this paper has been published and can be accessed via the original article. [ABSTRACT FROM AUTHOR]

Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for the treatment (Tx) of patients (pts) with R/R LBCL with ≥ 2 prior systemic therapies. In Cohorts 1+2 (C1+2) of the ZUMA-1 study, Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 11% and 32% of pts, respectively (Locke FL et al, Lancet Oncol 2019). A nonrandomized safety expansion cohort (Cohort 4 [C4]) evaluated the impact of earlier steroid use on CRS and NE rates. Here we present the primary analysis of ZUMA-1 C4 with a greater number of pts and longer follow-up (F/U). Eligible pts were leukapheresed, could receive optional bridging chemotherapy (not allowed in C1+2), and received conditioning chemotherapy before axi-cel infusion at a targeted 2 × 106 anti-CD19 CAR T cells/kg. C4 pts received early steroid intervention at Grade 1 NE and at Grade 1 CRS after 3 days of supportive care. Primary endpoints were incidence and severity of CRS and NEs. ORR and CAR T cell levels were compared across quartiles of tumor burden (TB). As of May 6, 2019, 41 pts had received axi-cel, with a median F/U of 8.7 mo. Pts who received bridging therapy prior to axi-cel (68%) all had evidence of disease after bridging, documented by a new baseline PET/CT scan. The median age was 61 y (range, 19 – 77 y; 32% ≥ 65 y). The majority of pts (63%) had DLBCL; 49% had an ECOG 1; 70% had disease stage III/IV; 68% were refractory to ≥ 2nd-line therapy; 63% had ≥ 3 prior lines of therapy; and 20% had relapsed after ASCT. C4 pts had a lower median TB by sum of product diameters (SPD; C4: 2100 mm2; C1+2: 3723 mm2) and lower pre-Tx serum LDH level than C1+2 pts. A greater proportion of C4 pts received steroids and tocilizumab vs C1+2 (73% and 76% vs 27% and 43%). Fewer C4 pts experienced Grade ≥ 3 CRS (2%) and NE (17%) than C1+2 pts. The ORR in C4 was 73% with a CR rate of 51%. Response was ongoing in C4 54% of pts with ≥ 6 mo F/U vs the 44% ongoing response rate at the primary analysis of C1+2 (also ≥ 6 mo F/U). Although most pts in C4 had lower SPDs than those in C1+2, responses were comparable when evaluated by TB. Median DOR was 8.9 mo, consistent with that observed for C1+2 (8.1 mo; Locke, AACR 2017; Figure). Median PFS was 11.7 mo; median OS was not reached. Peak CAR T cell levels were 42 cells/µL blood in C1+2 vs 59 cells/µL in C4. C1+2 had a median CAR AUC of 462 cells/µL × days vs 512 cells/µL in C4. CAR T cell expansion was comparable between cohorts when adjusted by TB. Levels of key NE-associated biomarkers including ferritin (pre- and post-Tx) and IL-2 (post-Tx) appeared lower in C4 than in C1+2. Earlier steroid use may reduce the rates of CAR T cell Tx-related CRS and NEs without affecting efficacy. Conclusions are limited by the nonrandomized study design and differences in population sizes and baseline characteristics between cohorts. Optimizing AE management is important to improve the benefit–risk profile of CAR T cell therapy. [ABSTRACT FROM AUTHOR]

Outcomes with salvage regimens in pts with MCL who progress after Bruton tyrosine kinase inhibitor (BTKi) therapy are poor. ZUMA-2 is a Phase 2, registrational, multicenter study evaluating KTE-X19, an autologous anti-CD19 CAR T cell therapy, in pts with R/R MCL (1-5 therapies, including a BTKi). We present interim efficacy and safety results. Evaluate efficacy and safety of KTE-X19 in R/R MCL. Eligible pts (≥ 18 y) with R/R MCL had an ECOG of 0-1 and ≤ 5 prior therapies, including chemotherapy, an anti-CD20 antibody, and a BTKi. Pts underwent leukapheresis and conditioning chemotherapy followed by KTE-X19 infusion at 2 × 106 cells/kg. Bridging therapy with dexamethasone, ibrutinib, or acalabrutinib was permitted. The primary endpoint was objective response rate (ORR; complete response [CR] + partial response) assessed by an Independent Review Committee per the Lugano Classification (Cheson, et al. J Clin Oncol. 2014). Interim efficacy endpoints were investigator-assessed using the revised IWG Response Criteria for Malignant Lymphoma (Cheson, et al. J Clin Oncol. 2007). Key secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), frequency of adverse events (AEs), and blood levels of CAR T cells and cytokines. Sixty pts received KTE-X19; here, we present results in pts with ≥ 1 y follow-up. Updated results in all 60 pts will be reported in the presentation. As of May 30, 2018, 28 pts received KTE-X19 with ≥ 1 y follow-up (median, 13.2 mo). The median age was 65 y; 43% of pts had an ECOG score of 1; 21% had blastoid morphology; 82% had stage IV disease; 50% had intermediate/high-risk MIPI; and 86% received a median of 4 prior therapies. In 20 of 28 pts with available data, the median Ki-67 index was 38%. Eight pts received bridging therapy; all had disease present post-bridging. Investigator-assessed ORR was 86% (95% CI, 67-96) with a CR rate of 57% (95% CI, 37-76). As of May 30, 2018, 75% of responders remained in response, and 64% of treated pts had ongoing responses. The 12-month rates of DOR, PFS, and OS were 83% (95% CI, 60-93), 71% (95% CI, 50-84), and 86% (95% CI, 66-94), respectively; medians were not reached. The most common Grade ≥ 3 AEs were anemia (54%), platelet count decreased (39%), and neutropenia (36%). Grade 3/4 cytokine release syndrome (CRS) assessed by Lee et al. (Blood. 2014) and Grade 3/4 neurologic events (NE) occurred in 18% and 46% of pts, respectively, with no Grade 5 events. CRS and NE were generally reversible. There was 1 Grade 5 AE of organizing pneumonia. Median CAR T cell levels measured by peak and area under the curve were 99 cells/µL (range, 0.4-2589) and 1542 cells/µL (range, 5.5-27239), respectively. With ≥ 1 y follow-up, KTE-X19 demonstrated significant and durable clinical benefit, with a manageable safety profile in pts with R/R MCL for whom there are no curative treatment options. [ABSTRACT FROM AUTHOR]