Antigen-independent, autonomous B cell receptor signaling drives activated B cell DLBCL.

Diffuse large B cell lymphoma of activated B cell type (ABC-DLBCL), a major cell-of-origin DLBCL subtype, is characterized by chronic active B cell receptor (BCR) signaling and NF-κB activation, which can be explained by activating mutations of the BCR signaling cascade in a minority of cases. We demonstrate that autonomous BCR signaling, akin to its essential pathogenetic role in chronic lymphocytic leukemia (CLL), can explain chronic active BCR signaling in ABC-DLBCL. 13 of 18 tested DLBCL-derived BCR, including 12 cases selected for expression of IgM, induced spontaneous calcium flux and increased phosphorylation of the BCR signaling cascade in murine triple knockout pre-B cells without antigenic stimulation or external BCR crosslinking. Autonomous BCR signaling was associated with IgM isotype, dependent on somatic BCR mutations and individual HCDR3 sequences, and largely restricted to non-GCB DLBCL. Autonomous BCR signaling represents a novel immunological oncogenic driver mechanism in DLBCL originating from individual BCR sequences and adds a new dimension to currently proposed genetics- and transcriptomics-based DLBCL classifications.

The Genetic Profile of Large B-Cell Lymphomas Presenting in the Ocular Adnexa.

To provide insights into targetable oncogenic pathways, this retrospective cohort study investigated the genetic profile of 26 patients with diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS), and two patients with high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL) presenting in the ocular adnexa. Pathogenic variants and copy number variations in 128 B-cell lymphoma-relevant genes were analyzed by targeted next-generation sequencing. Genetic subtypes were determined with the LymphGen algorithm. Primary ocular adnexal DLBCL-NOS constituted 50% (n = 14) and was generally characterized by non-germinal center B-cell origin (non-GCB) (n = 8, 57%), and LymphGen MCD subtype (n = 5, 36%). Primary ocular adnexal DLBCL-NOS presented pathogenic variants in genes involved in NF-κB activation and genes which are recurrently mutated in other extranodal lymphomas of non-GCB origin, including MYD88 (n = 4, 29%), CD79B (n = 3, 21%), PIM1 (n = 3, 21%), and TBL1XR1 (n = 3, 21%). Relapsed DLBCL-NOS presenting in the ocular adnexa (n = 6) were all of non-GCB origin and frequently of MCD subtype (n = 3, 50%), presenting with a similar genetic profile as primary ocular adnexal DLBCL-NOS. These results provide valuable insights into genetic drivers in ocular adnexal DLBCL-NOS, offering potential applications in future precision medicine.

Sinonasal DLBCL: molecular profiling identifies subtypes with distinctive prognosis and targetable genetic features.

ABSTRACT: Primary sinonasal diffuse large B-cell lymphoma (PSDLBCL) is a rare lymphoma with a variable prognosis and a unique relapse/dissemination pattern involving the central nervous system and skin. The underlying molecular mechanisms leading to this heterogeneity and progression pattern remain uncharted, hampering patient-tailored treatment. To investigate associated mechanisms, we analyzed clinical data and used immunohistochemistry, gene-expression profiling, cytogenetics, and next-generation sequencing in a cohort of 117 patients with PSDLBCL. The distribution in cell-of-origin (COO) was 68 (58%) activated B-cell (ABC), 44 (38%) germinal center B-cell (GCB), and 5 (4%) unclassifiable. COO was significantly associated with progression-free survival (PFS) and lymphoma-specific mortality (LSM) in both the overall cohort (5-year PFS: ABC, 43% vs GCB, 73%; LSM: ABC, 45% vs GCB, 14%) and in the subgroup of patients receiving immunochemotherapy (5-year PFS: ABC, 55% vs GCB, 85%; LSM: ABC, 28% vs GCB, 0%). ABC lymphomas were mainly MCD class, showing a high prevalence of MYD88 (74%) and CD79B (35%) mutations compared with GCB lymphomas (MYD88 23%; CD79B 10%) (P < .01). The ABC subtype frequently displayed cMYC/BCL2 coexpression (76% vs 18% GCB; P < .001) and HLA-II loss (48% vs 10% GCB; P < .001). PD-L1 expression and copy-number alterations were rare. All lymphomas were Epstein-Barr virus-negative. Our data suggest molecular profiling as a potent tool for detecting prognostic subgroups in PSDLBCL, exposing links to known relapse/dissemination sites. The ABC subgroup's MCD genetic features, shared with lymphomas at other nonprofessional lymphoid sites, make them potential candidates for targeted B-cell and toll-like receptor signaling therapy.

Autonomous B-cell receptor signaling and genetic aberrations in chronic lymphocytic leukemia-phenotype monoclonal B lymphocytosis in siblings of patients with chronic lymphocytic leukemia.

Clonal expansion of CD5-expressing B cells, commonly designated as monoclonal B lymphocytosis (MBL), is a precursor condition for chronic lymphocytic leukemia (CLL). The mechanisms driving subclinical MBL B-cell expansion and progression to CLL, occurring in approximately 1% of affected individuals, are unknown. An autonomously signaling B-cell receptor (BCR) is essential for the pathogenesis of CLL. The objectives of this study were functional characterization of the BCR of MBL in siblings of CLL patients and a comparison of genetic variants in MBL-CLL sibling pairs. Screening of peripheral blood by flow cytometry detected 0.2-480 clonal CLL-phenotype cells per microliter (median: 37/µL) in 34 of 191 (17.8%) siblings of CLL patients. Clonal BCR isolated from highly purified CLL-phenotype cells induced robust calcium mobilization in BCR-deficient murine pre-B cells in the absence of external antigen and without experimental crosslinking. This autonomous BCR signal was less intense than the signal originating from the CLL BCR of their CLL siblings. According to genotyping by single nucleotide polymorphism array, whole exome, and targeted panel sequencing, CLL risk alleles were found with high and similar prevalence in CLL patients and MBL siblings, respectively. Likewise, the prevalence of recurrent CLL-associated genetic variants was similar between CLL and matched MBL samples. However, copy number variations and small variants were frequently subclonal in MBL cells, suggesting their acquisition during subclinical clonal expansion. These findings support a stepwise model of CLL pathogenesis, in which autonomous BCR signaling leads to a non-malignant (oligo)clonal expansion of CD5+ B cells, followed by malignant progression to CLL after acquisition of pathogenic genetic variants.

Population-Based External Validation of the EASIX Scores to Predict CAR T-Cell-Related Toxicities.

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.

Real-world routine diagnostic molecular analysis for TP53 mutational status is recommended over p53 immunohistochemistry in B-cell lymphomas.

Previous studies in patients with mature B-cell lymphomas (MBCL) have shown that pathogenic TP53 aberrations are associated with inferior chemotherapeutic efficacy and survival outcomes. In solid malignancies, p53 immunohistochemistry is commonly used as a surrogate marker to assess TP53 mutations, but this correlation is not yet well-established in lymphomas. This study evaluated the accuracy of p53 immunohistochemistry as a surrogate marker for TP53 mutational analysis in a large real-world patient cohort of 354 MBCL patients within routine diagnostic practice. For each case, p53 IHC was assigned to one of three categories: wild type (staining 1-50% of tumor cells with variable nuclear staining), abnormal complete absence or abnormal overexpression (strong and diffuse staining > 50% of tumor cells). Pathogenic variants of TP53 were identified with a targeted next generation sequencing (tNGS) panel. Wild type p53 expression was observed in 267 cases (75.4%), complete absence in twenty cases (5.7%) and the overexpression pattern in 67 cases (18.9%). tNGS identified a pathogenic TP53 mutation in 102 patients (29%). The overall accuracy of p53 IHC was 84.5% (95% CI 80.3-88.1), with a robust specificity of 92.1% (95% CI 88.0- 95.1), but a low sensitivity of 65.7% (95% CI 55.7-74.8). These results suggest that the performance of p53 IHC is insufficient as a surrogate marker for TP53 mutations in our real-world routine diagnostic workup of MBCL patients. By using p53 immunohistochemistry alone, there is a significant risk a TP53 mutation will be missed, resulting in misevaluation of a high-risk patient. Therefore, molecular analysis is recommended in all MBCL patients, especially for further development of risk-directed therapies based on TP53 mutation status.

Outcome of combined modality treatment in first-line for stage I(E) peripheral T-cell lymphoma; a nationwide population-based cohort study from the Netherlands.

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 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.

The Dutch CAR-T Tumorboard Experience: Population-Based Real-World Data on Patients with Relapsed or Refractory Large B-Cell Lymphoma Referred for CD19-Directed CAR T-Cell Therapy in The Netherlands.

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.

Genomic profiling of post-transplant lymphoproliferative disorders using cell-free DNA.

Diagnosing post-transplant lymphoproliferative disorder (PTLD) is challenging and often requires invasive procedures. Analyses of cell-free DNA (cfDNA) isolated from plasma is minimally invasive and highly effective for genomic profiling of tumors. We studied the feasibility of using cfDNA to profile PTLD and explore its potential to serve as a screening tool. We included seventeen patients with monomorphic PTLD after solid organ transplantation in this multi-center observational cohort study. We used low-coverage whole genome sequencing (lcWGS) to detect copy number variations (CNVs) and targeted next-generation sequencing (NGS) to identify Epstein-Barr virus (EBV) DNA load and somatic single nucleotide variants (SNVs) in cfDNA from plasma. Seven out of seventeen (41%) patients had EBV-positive tumors, and 13/17 (76%) had stage IV disease. Nine out of seventeen (56%) patients showed CNVs in cfDNA, with more CNVs in EBV-negative cases. Recurrent gains were detected for 3q, 11q, and 18q. Recurrent losses were observed at 6q. The fraction of EBV reads in cfDNA from EBV-positive patients was 3-log higher compared to controls and EBV-negative patients. 289 SNVs were identified, with a median of 19 per sample. SNV burden correlated significantly with lactate dehydrogenase levels. Similar SNV burdens were observed in EBV-negative and EBV-positive PTLD. The most commonly mutated genes were TP53 and KMT2D (41%), followed by SPEN, TET2 (35%), and ARID1A, IGLL5, and PIM1 (29%), indicating DNA damage response, epigenetic regulation, and B-cell signaling/NFkB pathways as drivers of PTLD. Overall, CNVs were more prevalent in EBV-negative lymphoma, while no difference was observed in the number of SNVs. Our data indicated the potential of analyzing cfDNA as a tool for PTLD screening and response monitoring.

A population-based study of transformed marginal zone lymphoma: identifying outcome-related characteristics.

Histological transformation of marginal zone lymphoma (tMZL) into diffuse large B-cell lymphoma is associated with poor outcomes. Clinical characteristics associated with transformation risk and outcome after transformation are largely unknown due to scarcity of data. In this population-based study, competing risk analyses were performed to elucidate clinical characteristics associated with developing transformation among 1793 MZL patients using the Netherlands Cancer Registry. Cox regression analyses were performed to elucidate clinical characteristics associated with risk of relapse and mortality after transformation. Transformation occurred in 75 (4%) out of 1793 MZL patients. Elevated LDH and nodal MZL subtype at MZL diagnosis were associated with an increased risk, and radiotherapy with a reduced risk of developing tMZL. Most tMZL patients received R-(mini)CHOP (n = 53, 71%). Age >60 years and (immuno)chemotherapy before transformation were associated with an increased risk of relapse and mortality after transformation. Two-year progression-free survival (PFS) and overall survival (OS) were 66% (95% CI 52-77%) and 75% (95% CI 62-85%) for R-(mini)CHOP-treated tMZL patients, as compared to a PFS and OS both of 41% (95% CI 19-63%) for patients treated otherwise. Our study offers comprehensive insights into characteristics associated with transformation and survival after transformation, thereby optimizing guidelines and patient counseling.

A significant proportion of classic Hodgkin lymphoma recurrences represents clonally unrelated second primary lymphoma.

Despite high cure rates in classic Hodgkin lymphoma (cHL), relapses are observed. Whether relapsed cHL represents second primary lymphoma or an underlying T-cell lymphoma (TCL) mimicking cHL is underinvestigated. To analyze the nature of cHL recurrences, in-depth clonality testing of immunoglobulin (Ig) and T-cell receptor (TCR) rearrangements was performed in paired cHL diagnoses and recurrences among 60 patients, supported by targeted mutation analysis of lymphoma-associated genes. Clonal Ig rearrangements were detected by next-generation sequencing (NGS) in 69 of 120 (58%) diagnoses and recurrence samples. The clonal relationship could be established in 34 cases, identifying clonally related relapsed cHL in 24 of 34 patients (71%). Clonally unrelated cHL was observed in 10 of 34 patients (29%) as determined by IG-NGS clonality assessment and confirmed by the identification of predominantly mutually exclusive gene mutations in the paired cHL samples. In recurrences of >2 years, ∼60% of patients with cHL for whom the clonal relationship could be established showed a second primary cHL. Clonal TCR gene rearrangements were identified in 14 of 125 samples (11%), and TCL-associated gene mutations were detected in 7 of 14 samples. Retrospective pathology review with integration of the molecular findings were consistent with an underlying TCL in 5 patients aged >50 years. This study shows that cHL recurrences, especially after 2 years, sometimes represent a new primary cHL or TCL mimicking cHL, as uncovered by NGS-based Ig/TCR clonality testing and gene mutation analysis. Given the significant therapeutic consequences, molecular testing of a presumed relapse in cHL is crucial for subsequent appropriate treatment strategies adapted to the specific lymphoma presentation.

BRAF V600E is associated with higher incidence of second cancers in adults with Langerhans cell histiocytosis.

In this retrospective study, BRAF mutation status did not correlate with disease extent or (event-free) survival in 156 adults with Langerhans cell histiocytosis. BRAFV600E was associated with an increased incidence of second malignancies, often comprising hematological cancers, which may be clonally related.

A non-randomized risk-adjusted comparison of lenalidomide + R-CHOP versus R-CHOP for MYC-rearranged DLBCL patients.

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.

Detection of Second Primary Lymphoma in Late Diffuse Large B-cell Lymphoma Recurrences.

Approximately one-third of patients with diffuse large B-cell lymphoma (DLBCL) relapse and often require salvage chemotherapy followed by autologous stem cell transplantation. In most cases, the clonal relationship between the first diagnosis and subsequent relapse is not assessed, thereby potentially missing the identification of second primary lymphoma. In this study, the clonal relationship of 59 paired DLBCL diagnoses and recurrences was established by next-generation sequencing-based detection of immunoglobulin gene rearrangements. Among 50 patients with interpretable results, 43 patients (86%) developed clonally related relapsed disease. This was observed in 100% of early recurrences (<2 years), 80% of the recurrences with an interval between 2 and 5 years, and 73% of late recurrences (≥5 years). On the other hand, 7 (14%) out of 50 patients displayed different dominant clonotypes in primary DLBCL and clinical recurrences, confirming the occurrence of second primary DLBCL; 37% of DLBCL recurrences that occurred ≥4 years after diagnosis were shown to be second primary lymphomas. The clonally unrelated cases were Epstein-Barr virus positive in 43% of the cases, whereas this was only 5% in the relapsed DLBCL cases. In conclusion, next-generation sequencing-based clonality testing in late recurrences should be considered in routine diagnostics to distinguish relapse from second primary lymphoma, as this latter group of patients with DLBCL may benefit from less-intensive treatment strategies.

Development of a Core Set of Patient- and Caregiver-Reported Signs and Symptoms to Facilitate Early Recognition of Acute Chimeric Antigen Receptor T-Cell Therapy Toxicities.

PURPOSE: Prompt recognition of acute chimeric antigen receptor T (CAR T)-cell-mediated toxicities is crucial because adequate and timely management can prevent or reverse potential life-threatening complications. In the outpatient setting, patients and informal caregivers have to recognize and report signs and symptoms marking these acute toxicities. This study provides a core set of patient- and caregiver-reported signs and symptoms (outcomes, P/CROs) and definitions of red flags warranting immediate action to include in a daily checklist for support at home, with the goal to make outpatient post-CAR T-cell care safer, optimize patient and caregiver support, and thereby facilitating an early discharge/hospital visit reduction strategy. METHODS: We performed a systematic review of phase II/III trials of US Food and Drug Administration-approved CAR T-cell products and selected all common and severe adverse events that could be translated into a P/CRO for inclusion in a two-round modified Delphi procedure. Eleven CAR T-cell-dedicated hematologists from the Dutch CAR T-cell tumorboard representing all treating centers selected P/CROs for inclusion in the core set and defined red flags. The final core set was evaluated with patients and caregivers. RESULTS: From nine clinical trials, 457 adverse events were identified of which 42 could be used as P/CRO. The final core set contains 28 items, including five signs for measurement via wearables and two signs for caregiver-performed assessments. CONCLUSION: This study provides a core set of P/CROs that can serve as a framework for (eHealth) tools that aim to enable patients and caregivers to more effectively recognize and report signs and symptoms of acute toxicities after CAR T-cell therapy, which will enhance safe outpatient treatment monitoring.

Genetic Stability of Driver Alterations in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type and Their Relapses: A Rationale for the Use of Molecular-Based Methods for More Effective Disease Monitoring.

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is a rare, aggressive cutaneous lymphoma with a 5-year disease-specific survival of only ~55%. Despite high response rates to initial immune-polychemotherapy, most patients experience a disease relapse. The genetic evolution of primary and relapsed/refractory disease has only scarcely been studied in PCDLBCL-LT patients. Therefore, in this retrospective cohort study, 73 primary/pre-treatment and relapsed/refractory biopsies of 57 patients with PCDLBCL-LT were molecularly characterized with triple FISH and targeted next-generation sequencing for 52 B-cell-lymphoma-relevant genes, including paired analysis in 16 patients. In this cohort, 95% of patients harboured at least one of the three main driver alterations (mutations in MYD88/CD79B and/or CDKN2A-loss). In relapsed/refractory PCDLBCL-LT, these oncogenic aberrations were persistently present, demonstrating genetic stability over time. Novel alterations in relapsed disease affected mostly CDKN2A, MYC, and PIM1. Regarding survival, only MYC rearrangements and HIST1H1E mutations were statistically significantly associated with an inferior outcome. The stable presence of one or more of the three main driver alterations (mutated MYD88/CD79B and/or CDKN2A-loss) is promising for targeted therapies addressing these alterations and serves as a rationale for molecular-based disease monitoring, improving response evaluation and early identification and intervention of disease relapses in these poor-prognostic PCDLBCL-LT patients.

Impact of rituximab on treatment outcomes of patients with angioimmunoblastic T-cell lymphoma; a population-based analysis.

BACKGROUND: Patients with angioimmunoblastic T-cell lymphoma (AITL) are treated with cyclophosphamide, doxorubicin, vincristine and prednisone with or without etoposide (CHO(E)P). In the majority of cases, Epstein-Barr virus (EBV)-positive B-cells are present in the tumour. There is paucity of research examining the effect of rituximab when added to CHO(E)P. In this nationwide, population-based study, we analysed the impact of rituximab on overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) of patients with AITL. METHODS: Patients with AITL diagnosed between 2014 and 2020 treated with ≥one cycle of CHO(E)P with or without rituximab were identified in the Netherlands Cancer Registry. Survival follow-up was up to 1st February 2022. Baseline characteristics, best response during first-line treatment and survival were collected. PFS was defined as the time from diagnosis to relapse or to all-cause-death. OS was defined as the time from diagnosis to all-cause-death. Multivariable analysis for the risk of mortality was performed using Cox regression. FINDINGS: Out of 335 patients, 146 patients (44%) received R-CHO(E)P. Rituximab was more frequently used in patients with a B-cell infiltrate (71% versus 89%, p < 0·01). The proportion of patients who received autologous stem cell transplantation (ASCT) was similar between CHO(E)P and R-CHO(E)P (27% versus 30%, respectively). The ORR and 2-year PFS for patients who received CHO(E)P and R-CHO(E)P were 71% and 78% (p = 0·01), and 40% and 45% (p = 0·12), respectively. The 5-year OS was 47% and 40% (p = 0·99), respectively. In multivariable analysis, IPI-score 3-5, no B-cell infiltrate and no ASCT were independent prognostic factors for risk of mortality, whereas the use of rituximab was not. INTERPRETATION: Although the addition of rituximab to CHO(E)P improved ORR for patients with AITL, the PFS and OS did not improve.

Impact of etoposide and ASCT on survival among patients aged <65 years with stage II to IV PTCL: a population-based cohort study.

Patients aged <65 years with peripheral T-cell lymphoma (PTCL) are treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Although the addition of etoposide (CHOEP) and consolidation with autologous stem cell transplantation (ASCT) are preferred in some countries, randomized trials are lacking. This nationwide population-based study assessed the impact of etoposide and ASCT on overall survival (OS) among patients aged 18 to 64 years with stage II to IV anaplastic large-cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), or PTCL not otherwise specified (NOS) diagnosed between 1989 and 2018 using the Netherlands Cancer Registry. Patients were categorized into 2 calendar periods, representing pre- and post-eras of etoposide and ASCT, respectively. A total of 1427 patients were identified (ALCL, 35%; AITL, 21%; and PTCL NOS, 44%). OS increased from 39% in the period from 1989 to 2009 to 49% in the period of 2009 to 2018 (P < .01). Five-year OS was superior for patients treated with CHOEP vs CHOP (64% and 44%, respectively; P < .01). When adjusted for subtype, International Prognostic Index score, and ASCT, the risk of mortality was similar between the 2 groups, except for patients with ALK+ ALCL, for whom the risk of mortality was 6.3 times higher when treated with CHOP vs CHOEP. Patients undergoing consolidation with ASCT had superior 5-year OS of 81% compared with 39% for patients not undergoing ASCT (P < .01), regardless of whether complete remission was achieved. In patients aged <65 years with advanced-stage ALK- ALCL, AITL, or PTCL, the use of ASCT consolidation, but not the addition of etoposide, was associated with improved OS.

Biological and Clinical Implications of Gene-Expression Profiling in Diffuse Large B-Cell Lymphoma: A Proposal for a Targeted BLYM-777 Consortium Panel as Part of a Multilayered Analytical Approach.

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.