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. 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

Life-prolonging treatment restrictions and outcomes in patients with cancer and COVID-19:an update from the Dutch Oncology COVID-19 Consortium

AIM OF THE STUDY: The coronavirus disease 2019 (COVID-19) pandemic significantly impacted cancer care. In this study, clinical patient characteristics related to COVID-19 outcomes and advanced care planning, in terms of non-oncological treatment restrictions (e.g. do-not-resuscitate codes), were studied in patients with cancer and COVID-19. METHODS: The Dutch Oncology COVID-19 Consortium registry was launched in March 2020 in 45 hospitals in the Netherlands, primarily to identify risk factors of a severe COVID-19 outcome in patients with cancer. Here, an updated analysis of the registry was performed, and treatment restrictions (e.g. do-not-intubate codes) were studied in relation to COVID-19 outcomes in patients with cancer. Oncological treatment restrictions were not taken into account. RESULTS: Between 27th March 2020 and 4th February 2021, 1360 patients with cancer and COVID-19 were registered. Follow-up data of 830 patients could be validated for this analysis. Overall, 230 of 830 (27.7%) patients died of COVID-19, and 60% of the remaining 600 patients with resolved COVID-19 were admitted to the hospital. Patients with haematological malignancies or lung cancer had a higher risk of a fatal outcome than other solid tumours. No correlation between anticancer therapies and the risk of a fatal COVID-19 outcome was found. In terms of end-of-life communication, 50% of all patients had restrictions regarding life-prolonging treatment (e.g. do-not-intubate codes). Most identified patients with treatment restrictions had risk factors associated with fatal COVID-19 outcome. CONCLUSION: There was no evidence of a negative impact of anticancer therapies on COVID-19 outcomes. Timely end-of-life communication as part of advanced care planning could save patients from prolonged suffering and decrease burden in intensive care units. Early discussion of treatment restrictions should therefore be part of routine oncological care, especially during the COVID-19 pandemic

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

Patients <65 years with peripheral T-cell lymphoma are treated with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP). While the addition of etoposide 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 18-64 years with stage II-IV anaplastic large T-cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), diagnosed between 1989-2018, utilizing the Netherlands Cancer Registry. Patients were categorized into two calendar periods, which represent the pre- and post-era of etoposide and ASCT implementation, respectively. A total of 1,427 patients were identified (35% ALCL, 21% AITL and 44% PTCL-NOS). OS increased from 39% in 1989-2009 to 49% in 2009-2018 (p<0·01). The 5-year OS was superior for patients treated with CHOEP, as compared to patients with CHOP (64% and 44%, respectively; p<0·01). When adjusted for subtype, IPI-score, and ASCT, the risk of mortality was similar between the two groups, except for ALK+ ALCL patients for whom risk of mortality was 6.3 times higher when treated with CHOP as compared to CHOEP. Patients consolidated with ASCT demonstrated a superior 5-year OS of 81% as compared to 39% for patients not receiving an ASCT (p<0·01), regardless of whether a complete remission was achieved. In patients <65 years with advanced stage ALK- ALCL, AITL and PTCL, the use of ASCT consolidation, but not the addition of etoposide, was associated with improved OS

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 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

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 ( = 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 = 0.04), and the EASIX approached statistical significance at infusion ( = 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

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

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