Blockade of the PD-1 axis has modest efficacy in diffuse large B-cell lymphoma (DLBCL), but data regarding LAG3 are sparse. The impact of LAG3 digital gene expression was tested in 309 patients with DLBCL treated with standard chemoimmunotherapy. Cellular distribution of LAG3 protein was determined by immunohistochemistry and flow cytometry. In tumor-infiltrating lymphocytes (TILs), LAG3 expression was highest on CD4+ regulatory T cells (Tregs) and was also highly expressed on CD8+ T cells compared with CD4+ non-Tregs (both P = .008). LAG3high TILs were enriched in PD-1 and TIM-3. LAG3 was also expressed on a proportion of malignant B cells, and these patients had significantly higher LAG3 messenger RNA in their biopsies (P = .03). LAG3high gene expression was associated with inferior survival in discovery/validation cohorts, independent of cell of origin and the international prognostic index. Patients who were PD-L1high were fivefold more likely to be LAG3high (P < .0001). Patients who were LAG3high/PD-L1high had an inferior progression-free survival (P = .011) and overall survival (P = .005) compared with patients who were LAG3low/PD-L1high. Digital spatial protein analysis confirms LAG3 expression on T cells and, surprisingly, tumor-associated macrophages (TAMs) at higher levels than found on CD20+ B cells in the tumor microenvironment. LAG3 is frequently expressed on CD4+ Tregs and CD8+ TILs, typically with other immune checkpoints, and is also present in a proportion of malignant B cells in DLBCL and in areas enriched for TAMs. LAG3high expression is associated with poor outcome independent of conventional prognosticators.

Key Points Practices in early-stage FL are variable and include radiation alone, systemic therapy, CMT, or observation. Each practice resulted in similar excellent outcomes; randomized trials are required to determine the optimal treatment.

Monitoring of NPM1 mutant (mut) measurable residual disease (MRD) in acute myeloid leukemia (AML) has an established role in patients treated with intensive chemotherapy. The European LeukemiaNet has defined molecular persistence at low copy number (MP-LCN) as MRD transcript level <1-2% with <1-log change between any 2 positive samples collected after the end of treatment (EOT). As the clinical impact of MP-LCN is unknown, we sought to characterize outcomes in patients with persistent NPM1mut MRD after EOT and identify factors associated with disease progression. Consecutive patients with newly diagnosed NPM1mut AML who received at least 2 cycles of intensive chemotherapy were included if NPM1mut MRD positive in the bone marrow at the EOT and not transplanted in first complete remission. One hundred patients were followed for a median of 23.5 months; 42% remained free of progression at 1 year: either spontaneously achieving complete molecular remission (30%) or retaining low-level NPM1mut transcript (12% for ≥12 months and 9% at last follow up). Forty percent met the criteria for MP-LCN. Pre-emptive salvage therapy was found to significantly prolong relapse-free survival. Risk factors associated with disease progression were concurrent FLT3-ITD at diagnosis and suboptimal MRD response (NPM1mut reduction <4.4-log) at EOT.

Thrombotic microangiopathy (TMA) is a microvascular occlusive disorder characterised by platelet aggregation, thrombocytopenia and end-organ damage. It is commonly idiopathic, although several drug classes, including cytotoxic chemotherapy, have been implicated. Several of cases of gemcitabine-induced TMA have been documented with incidence likely to increase with the escalating use of gemcitabine. We report the cases of two patients who developed TMA while on gemcitabine chemotherapy.

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Altered operation of the renin-angiotensin-aldosterone system (RAAS) and dietary sodium intake have been identified as independent risk factors for cardiac hypertrophy. The way in which sodium intake and the operation of the renin-angiotensin-aldosterone system interact in the pathogenesis of cardiac hypertrophy is poorly understood. The aims of this study were to investigate the cardiac effects of the renin-angiotensin system (RAS) blockade in the spontaneously hypertensive rat (SHR), using co-treatment with an angiotensin II receptor blocker (ARB) and an angiotensin-converting enzyme (ACE) inhibitor with different sodium intakes. Our experiments with SHR show that, at high levels of sodium intake (4.0%), aggressive RAS blockade treatment with candesartan (3 mg/kg) and perindopril (6 mg/kg) does not result in regression of cardiac hypertrophy. In contrast, RAS blockade coupled with reduced sodium diet (0.2%) significantly regresses cardiac hypertrophy, impairs animal growth and is associated with elevated plasma renin and dramatically suppressed plasma angiotensinogen levels. Histological analyses indicate that the differential effect of reduced sodium on heart growth during RAS blockade is not associated with any change in myocardial interstitial collagen, but reflects modification of cellular geometry. Dimensional measurements of enzymatically-isolated ventricular myocytes show that, in the RAS blocked, reduced sodium group, myocyte length and width were decreased by about 16-19% compared with myocytes from the high sodium treatment group. Our findings highlight the importance of 'titrating' sodium intake with combined RAS blockade in the clinical setting to optimise therapeutic benefit. IntroductionThe occurrence of cardiac hypertrophy is independently associated with increased cardiovascular morbidity and mortality.1 The development of cardiac hypertrophy is influenced by a variety of interacting genetic, haemodynamic, neurohumoral trophic and dietary factors.2 Myocardial remodelling during the hypertrophic growth response involves both cellular hypertrophy and interstitial fibrosis. There is an increase in the size of individual cardiomyocytes, the nature of which depends on the specific hypertrophic stimuli, and an increase in the collagen type 1 component of the extracellular matrix.

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Introduction: Hereditary transthyretin (ATTRv; v for variant) amyloidosis, also known as hATTR amyloidosis, is a progressive and fatal disease associated with rapid deterioration of physical function and patients' quality of life (QOL). Vutrisiran, a subcutaneously administered RNA interference (RNAi) therapeutic that reduces hepatic production of transthyretin, was assessed in patients with ATTRv amyloidosis with polyneuropathy in the pivotal HELIOS-A study. Methods: The phase 3 open-label HELIOS-A study investigated the efficacy and safety of vutrisiran in patients with ATTRv amyloidosis with polyneuropathy, compared with an external placebo group from the APOLLO study of the RNAi therapeutic patisiran. Measures of QOL and physical function were assessed. Results: At month 18, vutrisiran improved Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score (least squares mean difference [LSMD] in change from baseline [CFB]: -21.0; p = 1.84 9 10 -10