Introduction: Although in a phase III trial of extranodal MZL (EMZL) patients (pts) the combination of rituximab and chlorambucil had superior progression-free and event-free survival (PFS, EFS) compared to either drug given alone (Zucca et al. JCO 2016), there is no standard front-line therapy for MZL pts requiring systemic treatment, and no randomized trial specifically addressed initial treatment for the splenic (SMZL) and nodal (NMZL) MZL subtypes. BTK inhibitors have shown durable responses with a favorable benefit-risk profile for all MZL subtypes in the relapsed setting. The ongoing IELSG47/MALIBU phase II trial is exploring efficacy and safety of rituximab plus ibrutinib in untreated MZL, with a focus on EMZL. We report here a planned preliminary analysis of the response and toxicity in the exploratory cohort of SMZL and NMZL pts. Methods: Treatment was comprised of 8 rituximab doses (the first 4 weekly and the subsequent 4 monthly, all but the first given subcutaneously) in combination with ibrutinib (560 mg once daily) for 2 years. Response evaluation was planned at 6, 24 weeks, and 12, 18, and 24 months after treatment start and was performed using Matutes criteria in SMZL and Lugano Classification in NMZL. Results: Between October 2019 and June 2021, 45 pts (30 with SMZL and 15 with NMZL) were enrolled from 16 centers in France, Italy, and Switzerland. Median age was 68 years (range: 44–81), 17 pts were male (38%), 41 pts had stage IV (91%), and 17 had elevated LDH (38%). All SMZL and 9 (60%) NMZL pts had bone marrow involvement. The best objective response reached in the entire cohort at any time was complete response (CR) in 22 pts (49%) and partial response (PR) in 19 pts (42%). Of the 36 pts currently evaluable for response at 12 months, 18 (50%) had a CR and 15 (42%) had a PR, while 3 (8%) had disease progression. The median time to best response was 2 months (range: 1–20). At a median follow-up of 23 months, 7 pts relapsed (1 SMZL and 6 NMZL) with a median duration of response of 18 months (range: 1–28+); 3 pts died (due to SARS-CoV2 infection, ischemic stroke, and car accident, respectively). The 2-year overall survival (OS) rate was 92% (95% CI: 75–97), with no significant difference between SMZL and NMZL. Median PFS was 24 months in the NMZL subset and was not reached among SMZL pts (p = 0.0133). The 2-year PFS was 77% (95% CI: 59–88) in the whole cohort, 86% (95% CI: 62%–95%) in SMZL, and 59% (95% CI: 27–81) in NMZL. Treatment was generally well-tolerated, with the most frequent grade 3–4 adverse events being neutropenia (reported in nine pts [20%]) and cutaneous rash (reported in four pts [9%]). Grade 3 atrial fibrillation or hypertension were reported in one (2%) and two (4%) pts, respectively. Treatment was discontinued in 15 pts (33%) after a median of 8 months (range: 2–23): 3 due to progressive disease, 6 due to toxicities, 4 due to unrelated events (1 second primary tumor, 1 stroke, 1 car accident, 1 cold agglutinine disease) and 2 due to consent withdrawal. The research was funded by: The research was supported partially by Janssen (financial and drug supply) and Roche (drug supply) Keywords: extranodal non-Hodgkin lymphoma, indolent non-Hodgkin lymphoma, molecular targeted therapies Conflicts of interests pertinent to the abstract C. Thieblemont Honoraria: BMS, Gilead/Kyte, Novartis, Roche, Janssen, Incyte, Abbvie, Miltenyi A. Tedeschi Consultant or advisory role: Astrazeneca, Janssen, Beigene, Abbvie A. Stathis Consultant or advisory role: Janssen, Roche Research funding: Abbvie, ADC Therapeutics, Amgen, AstraZeneca, Bayer, Cellestia, Incyte, LoxoOncology, Merck, Novartis, Pfizer, Philogen, Roche Educational grants: AstraZeneca Other remuneration: Expert testimonies from Bayer, Eli/Lilly S. Luminari Consultant or advisory role: Jannsen, Novartis, Beigene, BMS, Gilead, Regeneron, Genmab, Incyte L. Arcaini Consultant or advisory role: Roche, Janssen-Cilag, Verastem, Incyte, EUSA Pharma, Celgene/Bristol Myers Squibb, Kite/Gilead, ADC Therapeutics Research funding: Gilead Sciences Other remuneration: Speakers' Bureau of EUSA Pharma, Novartis O. Casasnovas Consultant or advisory role: Roche, Takeda, BMS, Merck, Gilead, Janssen, ADC therapeutics, Incyte, Astra Zeneca Honoraria: Roche, Takeda, BMS, Merck, Gilead, Janssen, ADC therapeutics, Incyte, Astra Zeneca Research funding: Roche, Takeda, Gilead, Abbvie Educational grants: Roche, Takeda, Janssen, Abbvie E. Zucca Consultant or advisory role: from BeiGene, BMS/Celgene, Celltion Healthcare, Curis, Eli/Lilly, Incyte, Ipsen, Janssen, Kyte (a Gilead Company), Merck, Roche Research funding: AstraZeneca, BMS/Celgene, Incyte, Janssen, Merck and Roche Educational grants: Abbvie, BeiGene, Janssen and Roche. A. Conconi Consultant or advisory role: Regeneron Other remuneration: speaker fees from Roche, Abbvie, Incyte, Takeda, AstraZeneca
Introduction: Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous entity. The clinical course is variable, mutated genes are multiple with no unifying mechanism, essential regulatory pathways and surrounding microenvironments are diverse. We sought to provide a unifying view of SMZL by resolving its heterogeneity in subgroups sharing genomic abnormalities, pathway signatures and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. Methods: We studied 303 pathologically confirmed SMZL spleen samples collected through the IELSG46 multicenter, international study (NCT02945319). The study cohort was representative of SMZL in terms of demographics, clinical features and outcome. We carried out a genetic and phenotypic analysis, defined self-organized signatures, validated them in independent primary tumors meta-data and in genetically modified mouse models, and correlated them with outcome data. Results: We identified and validated two prominent and self-aggregating genetic clusters in SMZL, termed NNK (58% of cases, from NF-kB, NOTCH and KLF2 modules) and DMT (32% of cases, from DNA-damage response, MAPK and TLR modules). NNK-SMZLs were dominated by mutations of NF-κB (e.g., TNFAIP3, TRAF3, BIRC3), NOTCH (e.g., NOTCH2, NOTCH1, SPEN) and KLF2. DMT-SMZLs were characterized by mutations in DNA damage response pathway genes (e.g., TP53, ATM). Mutations in MAPK (e.g., BRAF) and TLR genes (e.g., MYD88, all involving positions other than p.L265) were also enriched in DMT-SMZLs (Figure A and B). These genetic clusters have distinct underpinning biology. NNK-SMZLs were enriched of IGHV1-2*04 allele usage and of 7q deletion, while conversely DMT-SMZLs were depleted of both of them (Figure C). NNK-SMZL expressed significantly higher levels of genes belonging to NOTCH2 pathway and of genes that are activated by non-canonical NF-κB transcription factors. Conversely, DMT-SMZL had a signature of TP53 and apoptosis impairment (Figure D). Digital cytometry and in situ profiling segregated two basic types of SMZL immune microenvironment termed inflamed SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and non-inflamed SMZL (50% of cases) (Figure E and F). The combination of molecular and phenotypic profiling allowed to sort out a high risk clinical subset of patients whose tumor was characterized by having both NNK genotype and ‘’inflamed’’ microenvironment (Figure G). The research was funded by: Swiss Cancer League, ID 3746, 4395 4660, and 4705, Bern, Switzerland; Research Advisory Board of the Ente Ospedaliero Cantonale, ABREOC 2019-22514, Bellinzona, Switzerland; European Research Council (ERC) Consolidator Grant CLLCLONE, ID: 772051; Swiss National Science Foundation, ID 320030_169670/1, 310030_192439, 320036_179318, Berne, Switzerland; Fondazione Ticinese Contro il Cancro; Fondazione Fidinam, Lugano, Switzerland; Nelia & Amadeo Barletta Foundation, Lausanne, Switzerland; Fond’Action, Lausanne, Switzerland; The Leukemia & Lymphoma Society, Translational Research Program, ID 6594-20, New York; AFRI, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Fondazione Dr. Ettore Balli. Keywords: Diagnostic and Prognostic Biomarkers, Indolent non-Hodgkin lymphoma, Pathology and Classification of Lymphomas Conflicts of interests pertinent to the abstract P. Ghia Honoraria: AbbVie, ArQule/MSD, AstraZeneca, Beigene, Celgene/Juno(BMS, Gilead, Janssen, Loxo/Lilly, Roche Research funding: AbbVie, AstraZeneca, Gilead, Janssen, Sunesis G. Gritti Consultant or advisory role: Takeda, IQvia, Gilead Sciences Research funding: Gilead Sciences Educational grants: Roche, Abbvie, Gilead Sciences, Abbvie A. Moccia Consultant or advisory role: Roche, Janssen and Takeda L. Scarfó Honoraria: AbbVie, AstraZeneca and Janssen D. Rossi Honoraria: AbbVie, AstraZeneca, Janssen Research funding: AbbVie, AstraZeneca, Janssen
Introduction: In geographical areas where ocular adnexal MALT lymphoma (OAML) is frequently associated with Chlamydia psittaci (Cp) infection, monotherapy with a 3-week regimen of doxycycline has been associated with an overall response rate (ORR) of 65% and a 2-year progression-free survival (PFS) of 60% (IELSG27 trial; Ferreri, et al. JCO 2012). However, successful Cp eradication has been achieved only in half of patients (pts), which strongly conditioned therapeutic results. This could be explained by the well-known prolonged persistence of Cp within macrophages under the form of elementary bodies, a metabolically inert condition, refractory to antibiotics. Accordingly, a prolonged exposure to effective antibiotics could result in a higher bacterial eradication rate and better lymphoma control. This hypothesis was tested in a multicentre phase II trial (IELSG39), where OAML pts were treated with a six-month regimen of doxycycline. Herein, we report primary endpoint results. Methods: HIV-negative adults with untreated stage-IEA OAML were enrolled and treated with doxycycline 100 mg twice daily for 4 weeks followed by 4 weeks rest, repeated for 3 times. Cp DNA was assessed by real-time PCR on tumor tissue at diagnosis and monitored on conjunctival swabs and PBMC every 6 months. Tumor response (orbit MRI & ophthalmologist exam) was assessed every 6 months. The primary endpoint was the 2-year PFS; the primary objective was to improve the 2-yr PFS achieved in the IELSG27 trial (60%; P0) to 75% (P1). To detect such a difference, 30 pts with Cp-positive OAML were required (one-sided test; α 5%; β 80%); whenever ≥17 pts with Cp-pos OAMZL were progression-free at 2 years, the experimental therapy would be considered effective. Results: 44 pts (median age 58 yo, range 31–85; male:female ratio 0.63) were enrolled between March 2013 and May 2016. Cp DNA was detected in 21 (64%) of 33 assessed pts; PCR analysis is ongoing in 11. Doxycycline was well tolerated; all pts completed the treatment in the planned time. The best objective response was complete in 14 pts and partial in 14, with an ORR of 64% (95% CI = 50–78). The median time to the best response was 9 months (range 3–34). The primary endpoint was met: 32 pts remain relapse-free at 2 years: 18 had a Cp-pos OAML, 7 were Cp-neg, and PCR results are pending in 7. At a median follow-up of 83 months (range 10–115), 23 pts remain relapse-free, with a 2- and 5-yr PFS of 75% (95% CI 74–77) and 55% (95% CI 49–59), respectively. Pts with Cp-pos OAML had a 2- and 5-yr PFS of 90% (95% CI 90–91) and 65% (95% CI 61–69). All pts are alive. Full data on bacterial eradication rate and monitoring will be presented at the congress. Conclusions: This six-month regimen of doxycycline was safe and effective in pts with stage-I OAML. This treatment achieved the predetermined efficacy threshold and compares favourably with the 3-week regimen used in the IELSG27 trial, suggesting that a prolonged exposure to antibiotics improves lymphoma control. Keywords: extranodal non-Hodgkin lymphoma, indolent non-Hodgkin lymphoma, Therapeutics and Clinical Trials in Lymphoma - Other No conflicts of interests pertinent to the abstract.
Pro‐urokinase is a natural plasminogen activator that displays a clot‐lysis activity through a fibrin‐dependent mechanism. It seems to be a promising agent for the treatment of coronary thrombosis. Like tissue‐type plasminogen activator and two‐chain urokinase‐type plasminogen activator, pro‐urokinase has a very short half‐life in circulation. It has been described that conjugation of serum albumin with pro‐urokinase in plasma may occur that could protect this protein from degradation. In this study we describe the insertion of an extra cysteine residue in the N‐terminal end of des‐(C11–K135)‐pro‐urokinase (Δ125‐proUK), a pro‐urokinase deletion mutant lacking amino acids 11–135. We have expressed and purified the new mutein [H5K, S9C, N10T]des‐(C11‐K135)‐pro‐urokinase (Cys‐Δ125‐pro‐urokinase) and chemically conjugated it with serum albumin via the extra cysteine of Cys‐Δ125‐pro‐urokinase. The purified conjugate obtained has a lower specific amidolytic activity (72000 U/mg) than unconjugated Cys‐Δ125‐pro‐urikinase (240000 U/mg) due to its higher molecular mass and has a similar fibrinolytic activity in a clot lysis test to that of Δ125‐pro‐urokinase. We established an ELISA to measure the concentration of the conjugate in plasma and to follow the pharmacokinetics of the conjugate in monkeys after bolus injection. The conjugate displays significant lysis of human plasma clots in vivo and a dramatic increase of the half‐life in the circulation, with respect to pro‐urokinase and Δ125‐pro‐urokinase. Therefore, preliminary biological characterisation of this conjugate indicates that it could be a good candidate to inject as a bolus, compared with the infusion regimen needed with pro‐urokinase.
Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and in genetically modified mouse models, and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.
PURPOSE The role of consolidation radiotherapy in patients with primary mediastinal B-cell lymphoma (PMBCL) is controversial. METHODS The IELSG37 trial, a randomized noninferiority study, aimed to assess whether irradiation can be omitted in patients with PMBCL with complete metabolic response (CMR) after induction immunochemotherapy. The primary end point was progression-free survival (PFS) at 30 months after random assignment. Patients with CMR were randomly assigned to observation or consolidation radiotherapy (30 Gy). With a noninferiority margin of 10% (assuming a 30-month PFS of 85% in both arms), a sample size of 540 patients was planned with 376 expected to be randomly assigned. RESULTS The observed events were considerably lower than expected; therefore, primary end point analysis was conducted when ≥95% of patients were followed for ≥30 months. Of the 545 patients enrolled, 268 were in CMR after induction and were randomly assigned to observation (n = 132) or radiotherapy (n = 136). The 30-month PFS was 96.2% in the observation arm and 98.5% in the radiotherapy arm, with a stratified hazard ratio of 1.47 (95% CI, 0.34 to 6.28) and absolute risk difference of 0.68% (95% CI, –0.97 to 7.46). The 5-year overall survival (OS) was 99% in both arms. Nonrandomized patients were managed according to local policies. Radiotherapy was the only treatment in 86% of those with Deauville score (DS) 4 and in 57% of those with DS 5. The 5-year PFS and OS of patients with DS 4 (95.8% and 97.5%, respectively) were not significantly different from those of randomly assigned patients. Patients with DS5 had significantly poorer 5-year PFS and OS (60.3% and 74.6%, respectively). CONCLUSION This study, the largest randomized trial of radiotherapy in PMBCL, demonstrated favorable outcomes in patients achieving CMR with no survival impairment for those omitting irradiation.
