Summary
Atrial fibrillation (AF) occurs in 5–9% of patients treated with ibrutinib for chronic lymphocytic leukaemia (CLL); the clinical consequences and optimal management are unclear. We ...retrospectively studied 56 CLL patients who received ibrutinib and developed AF. Median time to onset was 3·8 months. AF was persistent in 35/56 (62%) cases despite treatment. Clinical consequences included: three episodes of severe cardiac failure (one fatal) and one stroke; eight non‐thrombocytopenic patients (14%) experienced severe bleeding adverse events. Altogether, ibrutinib was permanently discontinued in 26/56 cases (46%). Data to guide optimal management are lacking and clinical practice guidelines are urgently needed.
To assess the effectiveness and safety of rituximab alone or in combination with chlorambucil for the treatment of translocation (11;18)-negative gastric MALT lymphoma, we included 71 patients in a ...retrospective case-control study, 54 treated with rituximab alone and 17 with combination therapy. There was no difference between the groups in complete remission or overall response rates at weeks 25 and 52. After a median follow-up period of 5.8 years (range, 3.3 − 9.7 years), the 5-year progression-free survival probabilities were 60% and 88% in patients treated with rituximab monotherapy and combination therapy, respectively (p = .05). Adverse events were reported in 13 (18%) patients and were more frequent in the combination therapy group (p < .001). Combination therapy may be a preferable choice in patients with gastric MALT lymphoma irrespective of t(11;18) status. Further studies should assess benefit of stopping chlorambucil in early good-responder patients.
Mutational analyses performed following acquired ibrutinib resistance have suggested that chronic lymphocytic leukemia (CLL) progression on ibrutinib is linked to mutations in Bruton tyrosine kinase ...(BTK) and/or phospholipase Cγ2 (PLCG2) genes. Mutational information for patients still on ibrutinib is limited. We report a study aimed to provide a “snapshot” of the prevalence of mutations in a real-life CLL cohort still on ibrutinib after at least 3 years of treatment. Of 204 patients who initiated ibrutinib via an early-access program at 29 French Innovative Leukemia Organization (FILO) centers, 63 (31%) were still on ibrutinib after 3 years and 57 provided a fresh blood sample. Thirty patients had a CLL clone ≥0.5 × 109/L, enabling next-generation sequencing (NGS); BTK and PLCG2 mutations were detected in 57% and 13% of the NGS samples, respectively. After median follow-up of 8.5 months from sample collection, the presence of a BTK mutation was significantly associated with subsequent CLL progression (P = .0005 vs no BTK mutation). Our findings support that mutational analysis should be considered in patients receiving ibrutinib who have residual clonal lymphocytosis, and that clinical trials are needed to evaluate whether patients with a BTK mutation may benefit from an early switch to another treatment.
•In a real-life CLL cohort still on ibrutinib after 3 years, 57% of patients with residual clonal lymphocytosis had a BTK mutation.•The presence of a BTK mutation in patients still on ibrutinib conferred a greater likelihood of subsequent CLL progression.
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To determine recommended dose, dose-limiting toxicity, safety profile, pharmacokinetics, preliminary antitumor activity, and exploratory pharmacodynamics of SAR3419, an antibody-drug conjugate ...targeting CD19, administered alone by intravenous infusion weekly (qw), in a dose-escalation phase I study in patients with refractory/relapsed (R/R) non-Hodgkin lymphoma (NHL).
Patients with R/R CD19(+) B-NHL were treated with escalating doses of SAR3419 repeated qw for eight to 12 doses. On the basis of clinical evidence of late or cumulative toxicities, the study protocol was amended to test an "optimized" administration schedule consisting of four qw doses followed by four biweekly (q2w) doses (qw/q2w) at the recommended dose with the intent of reducing drug accumulation.
Forty-four patients were treated on seven dose levels ranging from 5 to 70 mg/m(2). SAR3419 recommended dose was determined as 55 mg/m(2) qw. Twenty-five patients received the qw/q2w schedule at 55 mg/m(2), which showed an improved safety profile compared with the qw schedule. Antilymphoma activity was observed with both schedules in around 30% of patients with either indolent or aggressive diseases. SAR3419 displayed a long terminal half-life (approximately 7 days) and a low clearance (approximately 0.6 L/d), with no dose effect. The qw/q2w schedule allowed limiting accumulation with a decrease in SAR3419 plasma trough and average concentrations by around 1.4-fold compared with the qw schedule.
While administered weekly, SAR3419 is well tolerated and active. The qw/q2w schedule that shows an improved safety profile and preserves antilymphoma activity is selected for clinical phase II studies.
COVID-19 patients affected by haematological malignancies have a more severe course of the disease and higher mortality, prompting for effective prophylaxis. The present study aims to evaluate the ...humoral response after mRNA vaccination as well as the impact of a third vaccine dose in patients with lymphoid malignancies.
We conducted a single-centre study, evaluating the serological responses of mRNA vaccination amongst a cohort of 200 patients affected by lymphoid malignancies after two or three doses using an industrial SARS-CoV-2 serology assay for anti-receptor binding domain (RBD) Spike IgG detection and quantification.
Among patients with plasma cell disorders, 59 of 96 (61%) had seroconversion (anti-RBD >50 AU/mL), and recent anti-CD38 therapies were associated with lower serological anti-RBD IgG concentrations (median IgG concentration 137 (IQR 0–512) AU/mL vs. 543 (IQR 35–3496) AU/mL; p < 0.001). Patients with B-cell malignancies had a lower seroconversion rate (20/84, 24%) mainly due to the broad usage of anti-CD20 monoclonal antibodies; only 2 of 53 (4%) patients treated by anti-CD20 antibodies during the last 12 months experienced a seroconversion. A total of 78 patients (44 with plasma cell disorders, 27 with B-cell malignancies, and 7 with other lymphomas) received a third dose of vaccine. The seroconversion rate and antibody concentrations increased significantly, especially in patients with plasma cell disorders, where an increment of anti-RBD IgG concentrations was observed in 31 of 44 (70%) patients, with an anti-RBD concentration median-fold increase of 10.6 (IQR 2.4–25.5). Its benefit in B-cell malignancies is uncertain, with only 2 of 25 (8%) patients having seroconverted after the vaccine booster, without increased median antibody concentration.
A third mRNA vaccine dose significantly improved humoral responses among patients with plasma cell disorders, whereas the effect was limited among patients with B-cell malignancies.
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Patients receiving anti-CD20 antibodies showed limited efficacy of a booster dose of BNT162b2. Patients with lymphomas combine such immunotherapies with cytotoxic chemotherapies that could result in ...an even greater alteration of the immune response to vaccination. We report here the impact of a third vaccine dose on T cell specific responses in a small cohort of patients treated in our center by anti-CD20 therapies and cytotoxic chemotherapies for lymphoid malignancies. Our results showed that a third dose in these severely immune suppressed patients could improve the expansion on CD4+Th1+T cell responses while the effect CD8 + T cell responses was marginal.
Enteropathy-associated T-cell lymphoma (EATL) is a rare but severe complication of coeliac disease (CeD), often preceded by low-grade clonal intraepithelial lymphoproliferation, referred to as type ...II refractory CeD (RCDII). Knowledge on underlying oncogenic mechanisms remains scarce. Here, we analysed and compared the mutational landscape of RCDII and EATL in order to identify genetic drivers of CeD-associated lymphomagenesis.
Pure populations of RCDII-cells derived from intestinal biopsies (n=9) or sorted from blood (n=2) were analysed by whole exome sequencing, comparative genomic hybridisation and RNA sequencing. Biopsies from RCDII (n=50), EATL (n=19), type I refractory CeD (n=7) and uncomplicated CeD (n=18) were analysed by targeted next-generation sequencing. Moreover, functional in vitro studies and drug testing were performed in RCDII-derived cell lines.
80% of RCDII and 90% of EATL displayed somatic gain-of-functions mutations in the JAK1-STAT3 pathway, including a remarkable p.G1097 hotspot mutation in the JAK1 kinase domain in approximately 50% of cases. Other recurrent somatic events were deleterious mutations in nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) regulators TNFAIP3 and TNIP3 and potentially oncogenic mutations in TET2, KMT2D and DDX3X. JAK1 inhibitors, and the proteasome inhibitor bortezomib could block survival and proliferation of malignant RCDII-cell lines.
Mutations activating the JAK1-STAT3 pathway appear to be the main drivers of CeD-associated lymphomagenesis. In concert with mutations in negative regulators of NF-κB, they may favour the clonal emergence of malignant lymphocytes in the cytokine-rich coeliac intestine. The identified mutations are attractive therapeutic targets to treat RCDII and block progression towards EATL.
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