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Abstract First-line treatment for advanced-stage diffuse large B-cell lymphoma (DLBCL) typically involves 6x R-CHOP21 or 6x R-CHOP21 with two additional rituximab administrations (6x R-CHOP21 + 2 R). In contemporary practice, this treatment choice might be guided by interim PET scan results. This nationwide, population-based study investigates the comparative effectiveness of these treatment regimens in an era where interim PET-guided treatment decisions were not standard practice. Utilizing the Netherlands Cancer Registry, we identified 1577 adult patients diagnosed with advanced-stage DLBCL between 2014–2018 who completed either 6x R-CHOP21 (43%) or 6x R-CHOP21 + 2 R (57%). We used propensity scores to assess differences in event-free survival (EFS) and overall survival (OS). At five years, EFS (hazard ratio of 6x R-CHOP21 + 2 R versus 6x R-CHOP21 [HR] = 0.89; 95% confidence interval [CI], 0.72–1.09) and OS (HR = 0.93; 95% CI, 0.73–1.18) were not significantly different between both regimens. In exploratory risk-stratified analysis according to the International Prognostic Index (IPI), high-IPI patients (i.e., scores of 4-5) benefit most from 6x R-CHOP21 + 2 R (5-year absolute risk difference of EFS = 16.8%; 95% CI, −0.4%−34.1% and OS = 12.1%; 95% CI, −5.4–29.6%). Collectively, this analysis reveals no significant differences on average in EFS and OS between the two treatments. However, the potential benefits for high-risk patients treated with 6x R-CHOP21 + 2 R underscore the need for future research.

Abstract MYD88 is the key signaling adaptor-protein for Toll-like and interleukin-1 receptors. A somatic L265P mutation within the Toll/interleukin-1 receptor (TIR) domain of MYD88 is found in 90% of Waldenström macroglobulinemia cases and in a significant subset of diffuse large B-cell lymphomas. MYD88-L265P strongly promotes NF-κB pathway activation, JAK-STAT signaling and lymphoma cell survival. Previous studies have identified other residues of the TIR-domain crucially involved in NF-κB activation, including serine 257 (S257), indicating a potentially important physiological role in the regulation of MYD88 activation. Here, we demonstrate that MYD88 S257 is phosphorylated in B-cell lymphoma cells and that this phosphorylation is required for optimal TLR-induced NF-κB activation. Furthermore, we demonstrate that a phosphomimetic MYD88-S257D mutant promotes MYD88 aggregation, IRAK1 phosphorylation, NF-κB activation and cell growth to a similar extent as the oncogenic L265P mutant. Lastly, we show that expression of MYD88-S257D can rescue cell growth upon silencing of endogenous MYD88-L265P expression in lymphoma cells addicted to oncogenic MYD88 signaling. Our data suggest that the L265P mutation promotes TIR domain homodimerization and NF-κB activation by copying the effect of MY88 phosphorylation at S257, thus providing novel insights into the molecular mechanism underlying the oncogenic activity of MYD88-L265P in B-cell malignancies.

Abstract Patients with MYC rearranged (MYC-R) diffuse large B-cell lymphoma (DLBCL) have a poor prognosis. Previously, we demonstrated in a single-arm phase II trial (HOVON-130) that addition of lenalidomide to R-CHOP (R2CHOP) is well-tolerated and yields similar complete metabolic remission rates as more intensive chemotherapy regimens in literature. In parallel with this single-arm interventional trial, a prospective observational screening cohort (HOVON-900) was open in which we identified all newly diagnosed MYC-R DLBCL patients in the Netherlands. Eligible patients from the observational cohort that were not included in the interventional trial served as control group in the present risk-adjusted comparison. R2CHOP treated patients from the interventional trial (n = 77) were younger than patients in the R-CHOP control cohort (n = 56) (median age 63 versus 70 years, p = 0.018) and they were more likely to have a lower WHO performance score (p = 0.013). We adjusted for differences at baseline using 1:1 matching, multivariable analysis, and weighting using the propensity score to reduce treatment-selection bias. These analyses consistently showed improved outcome after R2CHOP with HRs of 0.53, 0.51, and 0.59, respectively, for OS, and 0.53, 0.59, and 0.60 for PFS. Thus, this non-randomized risk-adjusted comparison supports R2CHOP as an additional treatment option for MYC-R DLBCL patients.

Peripheral T-cell lymphomas (PTCL) comprise a heterogeneous group of mature T-cell neoplasms with an unfavorable prognosis; presentation with stage I(E) disease is uncommon. In clinical practice, an abbreviated chemotherapy treatment regimen combined with radiotherapy (combined modality treatment [CMT]) is commonly used, although evidence from clinical trials is lacking. The aim of this nationwide population-based cohort study is to describe first-line treatment and outcome of patients with stage I(E) PTCL. All newly diagnosed patients ≥18 years with stage I(E) anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma NOS (PTCL not otherise specified [NOS]) in 1989-2020 were identified in the Netherlands Cancer Registry. Patients were categorized according to treatment regimen, i.e., chemotherapy (CT), radiotherapy (RT), CMT, other therapy and no treatment. The primary endpoint was overall survival (OS). Patients with stage I(E) ALCL, AITL and PTCL NOS (n=576) were most commonly treated with CMT (28%) or CT (29%), 2% underwent SCT. RT only was given in 18%, and 8% received other therapy and 16% no treatment. Overall, the 5-year OS was 59%. According to subtype, 5-year OS was superior for ALCL as compared to PTCL NOS and AITL (68% vs. 55% and 52%, respectively; P=0.03). For patients treated with CMT, 5-year OS was significantly higher (72%) as compared to patients treated with either CT or RT alone (55% and 55%, respectively; P

Abstract The paracaspase mucosa-associated lymphoid tissue 1 (MALT1) is a protease and scaffold protein essential in propagating B-cell receptor (BCR) signaling to NF-κB. The deubiquitinating enzyme cylindromatosis (CYLD) is a recently discovered MALT1 target that can negatively regulate NF-κB activation. Here, we show that low expression of CYLD is associated with inferior prognosis of diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) patients, and that chronic BCR signaling propagates MALT1-mediated cleavage and, consequently, inactivation and rapid proteasomal degradation of CYLD. Ectopic overexpression of WT CYLD or a MALT1-cleavage resistant mutant of CYLD reduced phosphorylation of IκBα, repressed transcription of canonical NF-κB target genes and impaired growth of BCR-dependent lymphoma cell lines. Furthermore, silencing of CYLD expression rendered BCR-dependent lymphoma cell lines less sensitive to inhibition of NF-κΒ signaling and cell proliferation by BCR pathway inhibitors, e.g., the BTK inhibitor ibrutinib, indicating that these effects are partially mediated by CYLD. Taken together, our findings identify an important role for MALT1-mediated CYLD cleavage in BCR signaling, NF-κB activation and cell proliferation, which provides novel insights into the underlying molecular mechanisms and clinical potential of inhibitors of MALT1 and ubiquitination enzymes as promising therapeutics for DLBCL, MCL and potentially other B-cell malignancies.

Abstract 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.

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.

The CD38-targeting antibody daratumumab has marked activity in multiple myeloma (MM). Natural killer (NK) cells play an important role during daratumumab therapy by mediating antibody-dependent cellular cytotoxicity via their FcγRIII receptor (CD16), but they are also rapidly decreased following initiation of daratumumab treatment. We characterized the NK cell phenotype at baseline and during daratumumab monotherapy by flow cytometry and cytometry by time of flight to assess its impact on response and development of resistance (DARA-ATRA study; NCT02751255). At baseline, nonresponding patients had a significantly lower proportion of CD16+ and granzyme B+ NK cells, and higher frequency of TIM-3+ and HLA-DR+ NK cells, consistent with a more activated/exhausted phenotype. These NK cell characteristics were also predictive of inferior progression-free survival and overall survival. Upon initiation of daratumumab treatment, NK cells were rapidly depleted. Persisting NK cells exhibited an activated and exhausted phenotype with reduced expression of CD16 and granzyme B, and increased expression of TIM-3 and HLA-DR. We observed that addition of healthy donor-derived purified NK cells to BM samples from patients with either primary or acquired daratumumab-resistance improved daratumumab-mediated MM cell killing. In conclusion, NK cell dysfunction plays a role in primary and acquired daratumumab resistance. This study supports the clinical evaluation of daratumumab combined with adoptive transfer of NK cells.

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.

Chimeric antigen receptor (CAR-) T cell therapy is a relatively new form of immunotherapy for hematological malignancies. Although patients are at increased risk of infection following CAR-T cell therapy, reports of fungal infections are scarce. We report a case of Scedosporium apiospermum infection causing bursitis of the elbow in a lymphoma patient after treatment with CAR-T cells. The fungal bursitis relapsed under posaconazole treatment, but was cured after surgical extirpation of the bursa.

BackgroundHIV testing among patients with malignant lymphoma (PWML) is variably implemented. We evaluated HIV testing among PWML, and mapped factors influencing hematologists' testing behavior.MaterialsWe 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.FindingsOverall, 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.ConclusionsMissed 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 It is unclear whether survival in diffuse large B-cell lymphoma (DLBCL) continues to increase in an era where rituximab-containing chemotherapy reigns for almost two decades. Therefore, we evaluated trends in primary therapy and relative survival (RS) among Dutch DLBCL patients diagnosed between 1989 and 2018. Analyses were performed separately according to the stage I (N = 6952) and stage II–IV disease (N = 20,676), stratified by calendar period and age (18–64, 65–74, and ≥75 years). The use of chemotherapy ± radiotherapy increased over time across all age and stage groups. As of the mid-2000s, >95% of chemotherapy-treated patients received chemoimmunotherapy, irrespective of age and stage. Overall, RS increased significantly over time across all age groups, especially after 2003 when rituximab-containing chemotherapy had become the standard of care. However, RS increased less pronounced between 2003–2010 and 2011–2018 than between 1989–2002 and 2003–2010. These findings were congruent across all studied stage groups. Five-year RS across the three age groups during 2011–2018 was 96%, 84%, and 67% for stage I DLBCL and 75%, 60%, and 46% for stage II–IV DLBCL. Collectively, survival in DLBCL increased modestly beyond the initial introduction of rituximab, with apparent survival differences across age and stage that warrant novel treatment approaches.

The real-world results of chimeric antigen receptor T-cell (CAR-T) therapy for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) substantially differ across countries. In the Netherlands, the CAR-T tumorboard facilitates a unique nationwide infrastructure for referral, eligibility assessment and data collection. The aim of this study was to evaluate real-world outcomes of axicabtagene ciloleucel (axi-cel) in the Dutch population, including the thus-far underreported effects on health-related quality of life (HR-QoL). All patients with R/R LBCL after ≥2 lines of systemic therapy referred for axi-cel treatment between May 2020–May 2022 were included (N = 250). Of the 160 apheresed patients, 145 patients received an axi-cel infusion. The main reason for ineligibility was rapidly progressive disease. The outcomes are better or at least comparable to other studies (best overall response rate: 84% (complete response: 66%); 12-month progression-free-survival rate and overall survival rate: 48% and 62%, respectively). The 12-month NRM was 5%, mainly caused by infections. Clinically meaningful improvement in several HR-QoL domains was observed from Month 9 onwards. Expert-directed patient selection can support effective and sustainable application of CAR-T treatment. Matched comparisons between cohorts will help to understand the differences in outcomes across countries and select best practices. Despite the favorable results, for a considerable proportion of patients with R/R LBCL there still is an unmet medical need.

Waldenström’s macroglobulinemia (WM), a rare low-grade B-cell non-Hodgkin lymphoma (NHL), has a distinct clinical presentation and different treatment-related side effects compared with other NHL. Currently, a wide variety of therapeutic agents are available for the treatment of WM but there is no consensus on optimal treatment in first line and/or at relapse. The aim of this survey was to evaluate the current knowledge and perspectives of hematologists on diagnosis and treatment of WM. Also, we compare these results to a similar survey done before the publication of the first Dutch national guideline, in order to evaluate the impact of the implementation of a national guideline. A link to an online survey was sent out to all registered hematologists and hemato-oncologists in the Netherlands with the request to participate. The survey contained questions regarding the preferred diagnostic and treatment methods in patients with WM as well as treatment goals. We also compared physicians preferred treatment goals to those of patients (as studied in a recent nationwide patient questionnaire). Ninety-five responses (30% response rate) were obtained, out of which 82 (86%) surveys were complete. The respondents most commonly used dexamethasone-rituximab-cyclophosphamide as first-line treatment. For second-line treatment, bendamustine with rituximab and ibrutinib monotherapy were the most frequently applied. Compared with the initial survey, serum IgM M-protein was determined in all cases, MYD88 mutation analysis was currently widely implemented, prevention of an IgM “flare” was uniformly managed by the respondents and use of rituximab-cyclophosphamide-vincristine-prednisone was entirely abandoned. Physicians differed somewhat from patients with regard to most important treatment goals. The approach to diagnostic methods and treatment options in WM was more consistent with international guidelines and was more homogeneous after implementation of the national guideline. These data indicate an increase in knowledge on WM diagnosis and treatment. This may have resulted from implementation of a local guideline or the global rise in awareness and attention for WM.

IgM monoclonal gammopathy of undetermined significance is a pre-malignant condition for Waldenström macroglobulinemia and other B-cell malignancies, defined by asymptomatic circulating IgM monoclonal protein below 30 g/L with a lymphoplasmacytic bone marrow infiltration of less than 10%. A significant proportion, however, develop unique immunological and biochemical manifestations related to the monoclonal protein itself in the absence of overt malignancy and are termed IgM-related disorders or, more recently, monoclonal gammopathy of clinical significance. The indication for treatment in affected patients is dictated by the pathological characteristics of the circulating IgM rather than the tumor itself. The clinical workup and treatment options vary widely and differ from those for Waldenström macroglobulinemia. The aim of this review is to alert clinicians to IgM monoclonal gammopathy of clinical significance and to provide practical guidance on when to screen for these phenotypes. We discuss clinical characteristics, the underlying clonal profile, diagnostic workup and treatment considerations for five important subtypes: cold agglutinin disease, type I and II cryoglobulinemia, IgM-associated peripheral neuropathy, Schnitzler syndrome and IgM-associated AL amyloidosis. The inhibition of the pathogenic effects of the IgM has led to great success in cold agglutinin disease and Schnitzler syndrome, whereas the other treatments are centered on eradicating the underlying clone. Treatment approaches in cryoglobulinemia and IgM-associated peripheral neuropathy are the least well developed. A multidisciplinary approach is required, particularly for IgM-related neuropathies and Schnitzler syndrome. Future work exploring novel, clone-directed agents and pathogenic IgM-directed therapies is welcomed.

Abstract Multiple myeloma (MM), a treatable but incurable malignancy, is characterized by the growth of clonal plasma cells in protective niches in the bone marrow. MM cells depend on expression of BCL-2 family proteins, in particular MCL-1, for survival. The regulation of MCL-1 is complex and cell type-dependent. Unraveling the exact mechanism by which MCL-1 is overexpressed in MM may provide new therapeutic strategies for inhibition in malignant cells, preferably limiting side effects in healthy cells. In this study, we reveal that one cause of overexpression could be stabilization of the MCL-1 protein. We demonstrate this in a subset of MM and diffuse large B cell lymphoma (DLBCL) cell lines and MM patient samples. We applied a phosphatase siRNA screen to identify phosphatases responsible for MCL-1 stabilization in MM, and revealed PP2A as the MCL-1 stabilizing phosphatase. Using the PP2A inhibitor okadaic acid, we validated that PP2A dephosphorylates MCL-1 at Ser159 and/or Thr163, and thereby stabilizes MCL-1 in MM cells with long MCL-1 half-life, but not in DLBCL cells. Combined kinase and phosphatase inhibition experiments suggest that the MCL-1 half-life in MM is regulated by the counteracting functions of JNK and PP2A. These findings increase the understanding of the mechanisms by which MCL-1 is post-translationally regulated, which may provide novel strategies to inhibit MCL-1 in MM cells.

Abstract 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 We assessed the impact of a prior malignancy diagnosis (PMD) – as a potential proxy for genetic cancer susceptibility – on the development of a second primary malignancy (SPM) and mortality in follicular lymphoma (FL) patients. From the nationwide Netherlands Cancer Registry, we selected all adult FL patients diagnosed in 1994‐2012 (n = 8028) and PMDs and SPMs relative to FL, with follow‐up until 2017. We constructed two Fine and Gray models – with death as a competing risk – to assess the association between a PMD and SPM incidence. A PMD was associated with an increased incidence of SPMs (subdistribution hazard ratio [SHR], 1.30; 95% confidence interval [CI], 1.03‐1.64) – especially carcinomas of the respiratory tract (SHR, 1.83; 95% CI, 1.10‐3.05) and cutaneous squamous cell carcinomas (SHR, 1.58; 95% CI, 1.01‐2.45) – and a higher risk of mortality in a multivariable model (HR, 1.43; 95% CI, 1.19‐1.71). However, when additionally adjusted for the receipt of systemic therapy and/or radiotherapy before FL diagnosis, only patients who received such therapies had an increased incidence of SPMs (SHR, 1.40; 95% CI, 1.02‐1.93). In conclusion, patients with a PMD had a higher rate of SPMs and mortality than those without a PMD, which might have resulted from therapy‐related carcinogenesis.

Abstract Background For patients with cancer, being well informed by their oncologist about treatment options and the implications thereof is highly relevant. Communication skills training (CST) programs have shown to be effective in improving clinicians’ communication skills, yet CSTs are time-consuming, inconvenient to schedule, and costly. Online education enables new ways of accessible learning in a safe and personalised environment. Aim and methods We describe the design of a digital CST-tool for information provision skills that meets oncologists’ learning needs. We used the CeHRes Roadmap for user-centred design as a guiding framework. Phase 1 (Contextual Inquiry) involved consultation of the literature and a focus group interview study to uncover the learning needs and training preferences of clinicians’ regarding a digital training for the skill of information-provision. In phase 2 (Value Specification), two multidisciplinary expert panels specified the learning content and format of a digital training. Phase 3 (Design) encompassed an iterative development process, including two user group assessment sessions and 5 individual user sessions in which prototypes were tested. All sessions were recorded and independently analyzed by two researchers. Results Based on literature and consultation of the users in the inquiry phase of the development process, and on expert opinion in the value specification phase, relevant (sub) skills and user requirements were defined to consider for the digital training format. It was decided to develop a conventional e-learning and a chatbot. Personalization and interactivity were integrated in the prototypes by including features that allow for e.g., choosing text, video or animation; to upload video-recorded consultations to receive peer-feedback; and to consult a communication expert. Results revealed that, overall, participants expressed a willingness to use a digital training tool to acquire information-provision skills. Individual user testing (including junior clinicians), indicated a preference for the chatbot over the e-learning. Conclusion We offer a description of extensive development work which was conducted in collaboration with multiple health care professionals to iteratively develop two innovative prototypes of digital tools that would appropriately engage oncologists in learning effective information giving skills. The resulting prototypes were well appreciated and thus provide a solid basis for further development and testing.

Antibody-mediated blockade of co-inhibitory molecules such as cytotoxic T lymphocyte-associated protein 4, PD1 and PDL1 elicits potent antitumor responses and improves the prognosis of many patients with cancer. As these immune checkpoint inhibitors (ICIs) are increasingly prescribed to a diverse patient population, a broad range of adverse effects is emerging. Atherosclerosis, a lipid-driven chronic inflammatory disease of the large arteries, may be aggravated by ICI treatment. In this review, we discuss recent clinical studies that analyze the correlation between ICI use and atherosclerotic cardiovascular disease (CVD). Indeed, several studies report an increased incidence of atherosclerotic CVD after ICI administration, with the occurrence of pathologies such as myocardial infarction, ischemic stroke and coronary artery disease significantly higher after ICI use. Increased awareness and better monitoring of ICI-treated patients can elucidate risk factors that contribute to ICI-induced aggravation of atherosclerosis and identify promising treatment strategies. For now, optimal cardiovascular risk assessment is required to protect ICI-receiving patients and long-term survivors of cancer from the detrimental effects of ICI therapy on atherosclerotic CVD.

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.

Since 2018, 2 chimeric antigen receptor (CAR) T-cell therapies received approval from the European Medicine Agency, with list prices around 320 000 Euro (€) (EUR) per treatment. These high prices raise concerns for patient access and the sustainability of healthcare systems. We aimed to estimate the costs and budget impact associated with CAR T-cell therapies for current and future indications in hematological cancers from 2019 to 2029. We focused on the former France, Germany, Spain, Italy and the United Kingdom (EU-5) and the Netherlands. We conducted a review of list prices, health technology assessment reports, budget impact analysis dossiers, and published cost-effectiveness analyses. We forecasted the 10-year health expenditures on CAR T-cells for several hematological cancers in selected European Union countries. Nine cost-effectiveness studies were identified and list prices for CAR T-cell therapies ranged between 307 200 EUR and 350 000 EUR. Estimated additional costs for pre- and post-treatment were 50 359 EUR per patient, whereas the incremental costs of CAR T-cell therapy (when compared with care as usual) ranged between 276 086 EUR and 328 727 EUR. We estimated market entry of CAR T-cell therapies for chronic mantle cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, multiple myeloma, and acute myeloid leukemia in 2021, 2022, 2022, 2022, and 2025, respectively. Cumulative expenditure estimates for existing and future indications from 2019 to 2029 were on average 28.5 billion EUR, 32.8 billion EUR, and 28.9 billion EUR when considering CAR T-cell therapy costs only, CAR T-cell therapy costs including pre- and post-treatment, and incremental CAR T-cell therapy costs, respectively. CAR T-cell therapies seem to be promising treatment options for hematological cancers but the financial burden on healthcare systems in the former EU-5 and the Netherlands will contribute to a substantial rise in healthcare expenditure in the field of hematology.

Achieving a metabolic complete response (mCR) before high-dose chemotherapy (HDC) and autologous peripheral blood stem-cell transplant (auto-PBSCT) predicts progression free survival (PFS) in relapsed/refractory classical Hodgkin lymphoma (R/R cHL). We added brentuximab vedotin (BV) to DHAP to improve the mCR rate. In a Phase I dose-escalation part in 12 patients, we showed that BV-DHAP is feasible. This Phase II study included 55 R/R cHL patients (23 primary refractory). Treatment consisted of three 21-day cycles of BV 1.8 mg/kg on day 1, and DHAP (dexamethasone 40mg days 1-4, cisplatin 100mg/m2; day 1 and cytarabine 2x2g/m2; day 2). Patients with a metabolic partial response (mPR) or mCR proceeded to HDC/auto-PBSCT. Based on independent central FDG-PET-CT review, 42 of 52 evaluable patients (81% [95% CI: 67-90]) achieved an mCR before HDC/auto-PBSCT, five had an mPR and five had progressive disease (three were not evaluable). After HDC/auto-PBSCT, four patients with an mPR converted to an mCR. The 2-year PFS was 74% [95% CI: 63-86], and the overall survival 95% [95% CI: 90-100]. Toxicity was manageable and mainly consisted of grade 3/4 hematological toxicity, fever, nephrotoxicity, ototoxicity (grade 1/2) and transiently elevated liver enzymes during BV-DHAP. Eighteen patients developed new onset peripheral neuropathy (maximum grade 1/2) and all recovered. In conclusion, BV-DHAP is a very effective salvage regimen in R/R cHL patients, but patients should be monitored closely for toxicity. ClinicalTrials.gov identifier: NCT02280993.

The 2016 World Health Organization classification defines diffuse large B-cell lymphoma (DLBCL) subtypes based on Epstein-Barr virus (EBV) infection and oncogenic rearrangements of MYC/BCL2/BCL6 as drivers of lymphomagenesis. A subset of DLBCL, however, is characterized by activating mutations in MYD88/CD79B. We investigated whether MYD88/CD79B mutations could improve the classification and prognostication of DLBCL. In 250 primary DLBCL, MYD88/CD79B mutations were identified by allele-specific polymerase chain reaction or next-generation-sequencing, MYC/BCL2/BCL6 rearrangements were analyzed by fluorescence in situ hybridization, and EBV was studied by EBV-encoded RNA in situ hybridization. Associations of molecular features with clinicopathologic characteristics, outcome, and prognosis according to the International Prognostic Index (IPI) were investigated. MYD88 and CD79B mutations were identified in 29.6% and 12.3%, MYC, BCL2, and BCL6 rearrangements in 10.6%, 13.6%, and 20.3%, and EBV in 11.7% of DLBCL, respectively. Prominent mutual exclusivity between EBV positivity, rearrangements, and MYD88/CD79B mutations established the value of molecular markers for the recognition of biologically distinct DLBCL subtypes. MYD88-mutated DLBCL had a significantly inferior 5-year overall survival than wild-type MYD88 DLBCL (log-rank; P=0.019). DLBCL without any of the studied aberrations had superior overall survival compared to cases carrying ≥1 aberrancy (log-rank; P=0.010). MYD88 mutations retained their adverse prognostic impact upon adjustment for other genetic and clinical variables by multivariable analysis and improved the prognostic performance of the IPI. This study demonstrates the clinical utility of defining MYD88-mutated DLBCL as a distinct molecular subtype with adverse prognosis. Our data call for sequence analysis of MYD88 in routine diagnostics of DLBCL to optimize classification and prognostication, and to guide the development of improved treatment strategies.

Chimeric antigen receptor (CAR) T cells are a novel class of anti-cancer therapy in which autologous or allogeneic T cells are engineered to express a CAR targeting a membrane antigen. In Europe, tisagenlecleucel (Kymriah™) is approved for the treatment of refractory/relapsed acute lymphoblastic leukemia in children and young adults as well as relapsed/refractory diffuse large B-cell lymphoma, while axicabtagene ciloleucel (Yescarta™) is approved for the treatment of relapsed/refractory high-grade B-cell lymphoma and primary mediastinal B-cell lymphoma. Both agents are genetically engineered autologous T cells targeting CD19. These practical recommendations, prepared under the auspices of the European Society of Blood and Marrow Transplantation, relate to patient care and supply chain management under the following headings: patient eligibility, screening laboratory tests and imaging and work-up prior to leukapheresis, how to perform leukapheresis, bridging therapy, lymphodepleting conditioning, product receipt and thawing, infusion of CAR T cells, short-term complications including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, antibiotic prophylaxis, medium-term complications including cytopenias and B-cell aplasia, nursing and psychological support for patients, long-term follow-up, post-authorization safety surveillance, and regulatory issues. These recommendations are not prescriptive and are intended as guidance in the use of this novel therapeutic class.

Abstract Background Adequate information-provision forms a crucial component of optimal cancer care. However, information-provision is particularly challenging in an oncology setting. It is therefore imperative to help oncological health care practitioners (HCP) optimise their information-giving skills. New forms of online education, i.e. e-learning, enable safe and time and location independent ways of learning, enhancing access to continuous learning for HCP. As part of a user-centred approach to developing an e-learning to improve information-giving skills, this study aims to: 1) uncover the learning needs of oncological healthcare providers related to information- provision, and 2) explore their training preferences in the context of clinical practice. Methods Focus groups and interviews were organised with oncological HCP (medical specialists and clinical nurse specialists) addressing participants’ learning needs concerning information- provision and their training preferences with respect to a new digital training tool on this issue. All sessions were audiorecorded and transcribed verbatim. Using an inductive approach, transcripts were independently coded by three researchers and discussed to reach consensus. Main themes were summarised and discussed. Results Four focus group sessions (total n = 13) and three interviews were conducted. The first theme concerned the patient outcomes HCP try to achieve with their information. We found HCP to mainly strive to promote patients’ understanding of information. The second theme concerned HCP reported strategies and challenges when trying to inform their patients. These entailed tailoring of information to patient characteristics, structuring of information, and dealing with patients’ emotions. Regarding HCP training preferences, an e-learning should be neatly connected to clinical practice. Moreover, participants desired a digital training to allow for feedback on their own (videotaped) information-giving skills from peers, communication experts, and/or patients; to monitor their progress and to tailored the training to individual learning needs. Conclusions An e-learning for improvement of information-giving skills of oncological HCP should be aimed at the transfer of skills to clinical practice, rather than at enhancing knowledge. Moreover, an e-learning is probably most effective when the facilitates individual learning needs, supports feedback on competence level and improvement, and allows input from significant others (experts, peers, or patients).

Patients with MYC-rearrangement positive large B-cell lymphoma (MYC+ LBCL) have an inferior prognosis following standard first-line therapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) as compared to patients without MYC rearrangement. Although intensive chemotherapy regimens yield higher remission rates, toxicity remains a concern. Lenalidomide is an oral immunomodulatory drug which downregulates MYC and its target genes thereby providing support using lenalidomide as additional therapeutic option for MYC+ LBCL. A phase II trial was conducted evaluating the efficacy of lenalidomide (15 mg day 1-14) in combination with R-CHOP (R2CHOP) in newly diagnosed MYC+ LBCL patients identified through a nationwide MYC-FISH screening program. The primary endpoint was complete metabolic response (CMR) on centrally reviewed 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)-computer tomography (CT)-scan at end-of-treatment. Secondary endpoints were overall survival (OS), disease-free survival (DFS) and event-free survival (EFS). Eighty-two patients with stage II-IV MYC+ LBCL were treated with 6 cycles of R2CHOP. At EOT, 67% (confidence interval (CI) 58-75%) of the patients reached CMR. With a median follow-up of 25.4 months, 2-year estimates (95% CI) for OS, DFS, EFS were 73% (62-82%), 75% (63-84%) and 63% (52-73%) respectively. In this prospective trial for newly diagnosed MYC+ LBCL patients, we found that administering R2CHOP was safe, and yields comparable CMR and survival rates as in studies applying more intensive chemotherapy regimens. Hence, these findings offer new prospects for MYC+ LBCL patients and warrant comparison in prospective randomized clinical trials. This trial was registered at www.clinicaltrialsregister.eu (#2014-002654-39).

More than 50 subtypes of B-cell non-Hodgkin lymphoma (B-NHL) are recognized in the most recent World Health Organization classification of 2016. The current treatment paradigm, however, is largely based on ‘one-size-fits-all’ immune-chemotherapy. Unfortunately, this therapeutic strategy is inadequate for a significant number of patients. As such, there is an indisputable need for novel, preferably targeted, therapies based on a biologically driven classification and risk stratification. Sequencing studies identified mutations in the MYD88 gene as an important oncogenic driver in B-cell lymphomas. MYD88 mutations constitutively activate NF-κB and its associated signaling pathways, thereby promoting B-cell proliferation and survival. High frequencies of the hotspot MYD88(L265P) mutation are observed in extranodal diffuse large B-cell lymphoma and Waldenström macroglobulinemia, thereby demonstrating this mutation’s potential as a disease marker. In addition, the presence of mutant MYD88 predicts survival outcome in B-NHL subtypes and it provides a therapeutic target. Early clinical trials targeting MYD88 have shown encouraging results in relapsed/refractory B-NHL. Patients with these disorders can benefit from analysis for the MYD88 hotspot mutation in liquid biopsies, as a minimally invasive method to demonstrate treatment response or resistance. Given these clear clinical implications and the crucial role of MYD88 in lymphomagenesis, we expect that analysis of this gene will increasingly be used in routine clinical practice, not only as a diagnostic classifier, but also as a prognostic and therapeutic biomarker directing precision medicine. This review focuses on the pivotal mechanistic role of mutated MYD88 and its clinical implications in B-NHL.

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.

An amendment to this paper has been published and can be accessed via the original article.

Although it is known that B-cell lymphomas occur more frequently in immunocompromised patients, thus far such an association has not been clearly established for T-cell lymphomas. Of the 251 patients who were diagnosed with a T-cell non-Hodgkin lymphoma in our center between 1999 and 2014, at least 25 were identified in immunocompromised patients. Herein, we retrospectively analyzed the clinical and pathological characteristics of these 25 cases. In addition, we searched the literature and present an overview of 605 previously published cases. The actual number of patients with B-cell chronic lymphocytic leukemia and patients on immunosuppressive drugs for inflammatory bowel disease or rheumatoid arthritis in the total cohort of 251 patients diagnosed with T-cell non-Hodgkin lymphoma was much higher than the number of patients expected to have these diseases in this cohort, based on their prevalence in the general population. This, together with the large number of additional cases found in the literature, suggest that the risk of developing T-cell non-Hodgkin lymphoma is increased in immunocompromised patients. Compared to T-cell non-Hodgkin lymphoma in the general population, these lymphomas are more often located extranodally, present at a younger age and appear to have a poor outcome. The observations made in the study herein should raise awareness of the possible development of T-cell non-Hodgkin lymphoma in immunodeficient patients, and challenge the prolonged use of immunosuppressive drugs in patients who are in clinical remission of their autoimmune disease.

Abstract. Chimeric antigen receptor (CAR)-T cell therapy is a new class of cellular immunotherapies that involves ex vivo genetic modification of T cells to incorporate an engineered CAR. After infusion into the patient, the CAR-expressing T cells recognize specific tumor targets and induce an immune response against them. The technology utilized is fundamentally different from previously available cancer treatments. Currently, most CAR-T cell therapies use autologous T cells. Tisagenlecleucel (formerly CTL019) is an anti-CD19 CAR-T cell therapy that was recently approved in the United States for the treatment of pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). Tisagenlecleucel has shown robust in vivo expansion and long-term persistence, clinically meaningful durable response and remission rates, and overall survival benefit in pediatric and young adult patients with relapsed/refractory B-ALL and in relapsed/refractory diffuse large B-cell lymphoma. Common adverse events (AEs) include cytokine release syndrome, which may require hospitalization and admission to an intensive care unit, neurological toxicities, and B-cell aplasia. These AEs are manageable when treated by an appropriately trained team. Additional research is required to further develop AE management protocols. In this review, we describe regulatory requirements, clinical considerations, and site-level requirements for clinical study implementation of CAR-T cell therapy in Europe. We also provide a case study of the European experience from the first global clinical trial for tisagenlecleucel, which may serve as a useful starting point for investigators and clinicians looking to implement CAR-T cell therapy at their institutions.

In follicular lymphoma, studies addressing the prognostic value of microenvironment-related immunohistochemical markers and tumor cell-related genetic markers have yielded conflicting results, precluding implementation in practice. Therefore, the Lunenburg Lymphoma Biomarker Consortium performed a validation study evaluating published markers. To maximize sensitivity, an end of spectrum design was applied for 122 uniformly immunochemotherapy-treated follicular lymphoma patients retrieved from international trials and registries. The criteria were: early failure, progression or lymphoma-related death 5 years. Immunohistochemical staining for T cells and macrophages was performed on tissue microarrays from initial biopsies and scored with a validated computer-assisted protocol. Shallow whole-genome and deep targeted sequencing was performed on the same samples. The 96/122 cases with complete molecular and immunohistochemical data were included in the analysis. EZH2 wild-type (P=0.006), gain of chromosome 18 (P=0.002), low percentages of CD8+ cells (P=0.011) and CD163+ areas (P=0.038) were associated with early failure. No significant differences in other markers were observed, thereby refuting previous claims of their prognostic significance. Using an optimized study design, this Lunenburg Lymphoma Biomarker Consortium study substantiates wild-type EZH2 status, gain of chromosome 18, low percentages of CD8+ cells and CD163+ area as predictors of early failure to immunochemotherapy in follicular lymphoma treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP [-like]), while refuting the prognostic impact of various other markers.