Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B)

Background The superiority of a chemotherapy with doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone (ACVBP) in comparison with cyclophosphamide, doxorubicin, vincristin and prednisone plus radiotherapy for young patients with localized diffuse large B-cell lymphoma (DLBCL) was previously demonstrated. We report the results of a trial which evaluates the role of rituximab combined with ACVBP (R-ACVBP) in these patients. Patients and methods Untreated patients younger than 66 years with stage I or II DLBCL and no adverse prognostic factors of the age-adjusted International Prognostic Index were randomly assigned to receive three cycles of ACVBP plus sequential consolidation with or without the addition of four infusions of rituximab. Results A total of 223 patients were randomly allocated to the study, 110 in the R-ACVBP group and 113 in the ACVBP group. After a median follow-up of 43 months, our 3-year estimate of event-free survival was 93% in the R-ACVBP group and 82% in the ACVBP group (P = 0.0487). Three-year estimate of progression-free survival was increased in the R-ACVBP group (95% versus 83%, P = 0.0205). Overall survival did not differ between the two groups with a 3-year estimates of 98% and 97%, respectively (P = 0.686). Conclusion In young patients with low-risk localized DLBCL, rituximab combined with three cycles of ACVBP plus consolidation is significantly superior to ACVBP plus consolidation alon

Real-world experience among patients with relapsed/refractory mantle cell lymphoma after Bruton tyrosine kinase inhibitor failure in Europe: The SCHOLAR-2 retrospective chart review study

Mantle cell lymphoma (MCL) after relapse is associated with poor prognosis. No standard of care exists and available evidence for treatments is limited, particularly in patients who fail Bruton tyrosine kinase inhibitor (BTKi) therapy. This multicentre retrospective chart review study, SCHOLAR-2, addresses this knowledge gap and reports on data collected from 240 patients with relapsed/refractory MCL in Europe who were treated with BTKi-based therapy between July 2012 and July 2018, and had experienced disease progression while on BTKi therapy or discontinued BTKi therapy due to intolerance. The median overall survival (OS) from initiation of first BTKi therapy was 14.6 months (95% confidence interval [CI] 11.6–20.0) in the overall cohort, 5.5 months (95% CI 3.9–8.2) in 91 patients without post-BTKi therapy, and 23.8 months (95% CI 18.9–30.1) in 149 patients who received post-BTKi therapy (excluding chimeric antigen receptor T-cell treatment). In the latter group, patients received a median of one (range, one to seven) line of post-BTKi therapy, with lenalidomide-containing regimens and bendamustine plus rituximab being the most frequently administered; the median OS from initiation of first post-BTKi therapy was 9.7 months (95% CI 6.3–12.7). These results provide a benchmark for survival in patients with R/R MCL receiving salvage therapy after BTKi failure

The MAGNOLIA Trial: Zanubrutinib, a Next-Generation Bruton Tyrosine Kinase Inhibitor, Demonstrates Safety and Efficacy in Relapsed/Refractory Marginal Zone Lymphoma

Purpose: Marginal zone lymphoma (MZL) is an uncommon non-Hodgkin lymphoma with malignant cells that exhibit a consistent dependency on B-cell receptor signaling. We evaluated the efficacy and safety of zanubrutinib, a next-generation selective Bruton tyrosine kinase inhibitor, in patients with relapsed/ refractory (R/R) MZL. Patients and Methods: Patients with R/R MZL were enrolled in the phase II MAGNOLIA (BGB-3111-214) study. The primary endpoint was overall response rate (ORR) as determined by an independent review committee (IRC) based on the Lugano 2014 classification. Results: Sixty-eight patients were enrolled. After a median follow-up of 15.7 months (range, 1.6 to 21.9 months), the IRCassessed ORR was 68.2% and complete response (CR) was 25.8%. The ORR by investigator assessment was 74.2%, and the CR rate was 25.8%. The median duration of response (DOR) and median progression-free survival (PFS) by independent review was not reached. The IRC-assessed DOR rate at 12 months was 93.0%, and IRC-assessed PFS rate was 82.5% at both 12 and 15 months. Treatment was well tolerated with the majority of adverse events (AE) being grade 1 or 2. The most common AEs were diarrhea (22.1%), contusion (20.6%), and constipation (14.7%). Atrial fibrillation/flutter was reported in 2 patients; 1 patient had grade 3 hypertension. No patient experienced major hemorrhage. In total, 4 patients discontinued treatment due to AEs, none of which were considered treatment-related by the investigators. Conclusions: Zanubrutinib demonstrated highORRand CR rate with durable disease control and a favorable safety profile in patients with R/R MZL. _2021 The Authors; Published by the American Association for Cancer Research

Oligomeric Structure of the MALT1 Tandem Ig-Like Domains

Mucosa-associated lymphoid tissue 1 (MALT1) plays an important role in the adaptive immune program. During TCR- or BCR-induced NF-κB activation, MALT1 serves to mediate the activation of the IKK (IκB kinase) complex, which subsequently regulates the activation of NF-κB. Aggregation of MALT1 is important for E3 ligase activation and NF-κB signaling.Unlike the isolated CARD or paracaspase domains, which behave as monomers, the tandem Ig-like domains of MALT1 exists as a mixture of dimer and tetramer in solution. High-resolution structures reveals a protein-protein interface that is stabilized by a buried surface area of 1256 Å(2) and contains numerous hydrogen and salt bonds. In conjunction with a second interface, these interactions may represent the basis of MALT1 oligomerization.The crystal structure of the tandem Ig-like domains reveals the oligomerization potential of MALT1 and a potential intermediate in the activation of the adaptive inflammatory pathway.This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1

Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B).

Background The superiority of a chemotherapy with doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone (ACVBP) in comparison with cyclophosphamide, doxorubicin, vincristin and prednisone plus radiotherapy for young patients with localized diffuse large B-cell lymphoma (DLBCL) was previously demonstrated. We report the results of a trial which evaluates the role of rituximab combined with ACVBP (R-ACVBP) in these patients. Patients and methods Untreated patients younger than 66 years with stage I or II DLBCL and no adverse prognostic factors of the age-adjusted International Prognostic Index were randomly assigned to receive three cycles of ACVBP plus sequential consolidation with or without the addition of four infusions of rituximab. Results A total of 223 patients were randomly allocated to the study, 110 in the R-ACVBP group and 113 in the ACVBP group. After a median follow-up of 43 months, our 3-year estimate of event-free survival was 93% in the R-ACVBP group and 82% in the ACVBP group (P = 0.0487). Three-year estimate of progression-free survival was increased in the R-ACVBP group (95% versus 83%, P = 0.0205). Overall survival did not differ between the two groups with a 3-year estimates of 98% and 97%, respectively (P = 0.686). Conclusion In young patients with low-risk localized DLBCL, rituximab combined with three cycles of ACVBP plus consolidation is significantly superior to ACVBP plus consolidation alone

Complications of Autologous Stem Cell Transplantation in Multiple Myeloma : Results from the CALM Study

Background: The main goal of this post hoc analysis of the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study was to evaluate the rate of short- and long-term infectious and non-infectious complications occurring after ASCT in patients with multiple myeloma (MM). Methods: The analysis included all patients with MM from the CALM study who underwent >= 1 ASCT. The primary endpoint of the analysis was to determine the rate of infectious and non-infectious complications after ASCT and to compare them in three time periods: 0-100 days, 101 days-1 year, and >1 year after the first transplant. Results: The analysis included a total of 3552 patients followed up for a median of 56.7 months (range 0.4-108.1). Complication rates decreased with the time from ASCT with 24.85 cases per 100 patient-years from day 0 to 100 days after the transplant, andPeer reviewe

Prophylactic corticosteroid use in patients receiving axicabtagene ciloleucel for large B-cell lymphoma

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

The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee

Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors

Treatment of Older Patients with Mantle-Cell Lymphoma

BACKGROUND: The long-term prognosis for older patients with mantle-cell lymphoma is poor. Chemoimmunotherapy results in low rates of complete remission, and most patients have a relapse. We investigated whether a fludarabine-containing induction regimen improved the complete-remission rate and whether maintenance therapy with rituximab prolonged remission. METHODS: We randomly assigned patients 60 years of age or older with mantle-cell lymphoma, stage II to IV, who were not eligible for high-dose therapy to six cycles of rituximab, fludarabine, and cyclophosphamide (R-FC) every 28 days or to eight cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 21 days. Patients who had a response underwent a second randomization to maintenance therapy with rituximab or interferon alfa, each given until progression. RESULTS: Of the 560 patients enrolled, 532 were included in the intention-to-treat analysis for response, and 485 in the primary analysis for response. The median age was 70 years. Although complete-remission rates were similar with R-FC and R-CHOP (40% and 34%, respectively; P=0.10), progressive disease was more frequent with R-FC (14%, vs. 5% with R-CHOP). Overall survival was significantly shorter with R-FC than with R-CHOP (4-year survival rate, 47% vs. 62%; P=0.005), and more patients in the R-FC group died during the first remission (10% vs. 4%). Hematologic toxic effects occurred more frequently in the R-FC group than in the R-CHOP group, but the frequency of grade 3 or 4 infections was balanced (17% and 14%, respectively). In 274 of the 316 patients who were randomly assigned to maintenance therapy, rituximab reduced the risk of progression or death by 45% (in remission after 4 years, 58%, vs. 29% with interferon alfa; hazard ratio for progression or death, 0.55; 95% confidence interval, 0.36 to 0.87; P=0.01). Among patients who had a response to R-CHOP, maintenance therapy with rituximab significantly improved overall survival (4-year survival rate, 87%, vs. 63% with interferon alfa; P=0.005). CONCLUSIONS: R-CHOP induction followed by maintenance therapy with rituximab is effective for older patients with mantle-cell lymphom