Systemic lupus erythematosus: one year in review 2023

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a wide range of clinical manifestations and a relapsing-remitting course. New data regarding pathogenic pathways, biomarkers and clinical manifestations of SLE are emerging, and new drugs and therapeutic protocols have been proposed to improve the control of disease activity. Furthermore, new insights into comorbidities and reproductive health in SLE patients are constantly emerging.This annual review aims to summarise the most relevant data on SLE that was published in 2022

Continous Treatment with Ibrutinib in 100 Untreated Patients with TP53 Disrupted Chronic Lymphocytic Leukemia. A Real-Life Campus CLL Study

Continous Treatment with Ibrutinib in 100 Untreated Patients with TP53 Disrupted Chronic Lymphocytic Leukemia. A Real-Life Campus CLL Stud

p66Shc deficiency in the Eμ-TCL1 mouse model of chronic lymphocytic leukemia enhances leukemogenesis by altering the chemokine receptor landscape

The Shc family adaptor p66Shc acts as a negative regulator of proliferative and survival signals triggered by the B Cell Receptor and, by enhancing the production of reactive oxygen species, promotes oxidative stress-dependent apoptosis. Additionally, p66Shc controls the expression and function of chemokine receptors that regulate lymphocyte traffic. Chronic lymphocytic leukemia cells have a p66Shc expression defect which contributes to their extended survival and correlates with poor prognosis. We have analyzed the impact of p66Shc ablation on disease severity and progression in the mouse model of chronic lymphocytic leukemia Eμ-TCL1. We show that Eμ-TCL1/p66Shc-/- mice develop an aggressive disease that has an earlier onset, a higher incidence and leads to earlier death compared to Eμ-TCL1 mice. Eμ-TCL1/p66Shc-/- mice display substantial leukemic cell accumulation in both nodal and extranodal sites. The target organ selectivity correlates with an upregulation of chemokine receptors whose ligands are expressed therein. This also applies to chronic lymphocytic leukemia cells, where chemokine receptor expression and extent of organ infiltration were found to inversely correlate with their p66Shc expression levels. p66Shc expression declined with disease progression in Eμ-TCL1 mice and could be restored by treatment with the Bruton tyrosine kinase inhibitor Ibrutinib. Our results highlight p66Shc deficiency as an important factor in chronic lymphocytic leukemia progression and severity and underscore p66Shc expression as a relevant therapeutic target

Targeted activation of the SHP-1/PP2A signaling axis elicits apoptosis of chronic lymphocytic leukemia cells

Lyn, a member of the Src family of kinases, is a key factor in the dys-regulation of survival and apoptotic pathways of malignant B cells in chronic lymphocytic leukemia. One of the effects of Lyn's action is spatial and functional segregation of the tyrosine phosphatase SHP-1 into two pools, one beneath the plasma membrane in an active state promoting pro-survival signals, the other in the cytosol in an inhibited conformation and unable to counter the elevated level of cytosolic tyrosine phosphorylation. We herein show that SHP-1 activity can be elicited directly by nintedanib, an agent also known as a triple angiokinase inhibitor, circumventing the phospho-S591-dependent inhibition of the phosphatase, leading to the dephosphorylation of pro-apoptotic players such as procaspase-8 and serine/threonine phosphatase 2A, eventually triggering apoptosis. Furthermore, the activation of PP2A by using MP07-66, a novel FTY720 analog, stimulated SHP-1 activity via dephosphorylation of phospho-S591, which unveiled the existence of a positive feedback signaling loop involving the two phosphatases. In addition to providing further insights into the molecular basis of this disease, our findings indicate that the PP2A/SHP-1 axis may emerge as an attractive, novel target for the development of alternative strategies in the treatment of chronic lymphocytic leukemia

Lyn sustains oncogenic signaling in chronic lymphocytic leukemia by strengthening SET-mediated inhibition of PP2A.

Aberrant protein kinase activities, and the consequent dramatic increase of Ser/Thr and -Tyr phosphorylation, promote the deregulation of the survival pathways in chronic lymphocytic leukemia (CLL), which is crucial to the pathogenesis and progression of the disease. In this study, we show that the tumor suppressor Protein Phosphatase 2A (PP2A), one of the major Ser/Thr phosphatase, is in an inhibited form due to the synergistic contribution of two events, the interaction with its physiological inhibitor SET and the phosphorylation of Y307 of the catalytic subunit of PP2A. The latter event is mediated by Lyn, a Src family kinase previously found to be overexpressed, delocalized and constitutively active in CLL cells. This Lyn/PP2A axis accounts for the persistent high level of phosphorylation of the phosphatase's targets and represents a key connection linking phosphotyrosine- and phosphoserine/threonine-mediated oncogenic signals. The data herein presented show that the disruption of the SET/PP2A complex by a novel FTY720-analogue (MP07-66) devoid of immunosuppressive effects leads to the reactivation of PP2A, which in turn triggers apoptosis of CLL cells. When used in combination with SFK inhibitors, the action of MP07-66 is synergistically amplified, providing a new option in the therapeutic strategy for CLL patients

Patients' preferences for chronic lymphocytic leukemia treatment: The CHOICE study

Chronic lymphocytic leukemia (CLL) therapies differ in efficacy, side effects, route, frequency, and duration of administration. We assessed patient preferences for treatment attributes and evaluated associations with disease stage, treatment line, and socio-demographic characteristics in a cross sectional, observational study conducted at 16 Italian hematology centers. Study visits occurred between February and July 2020; 401 adult patients with CLL (201 Watch and Wait (W & W), 200 treated) participated in a discrete choice experiment (DCE), composed of 8 choices between pairs of treatment profiles with different levels of 5 attributes of currently available CLL treatments (length of response, route and duration of administration, risk of side effects including diarrhea, infections, or organ damage). Health-related quality of life was assessed with the EQ-5D-5L, EORTC QLQ-C30 and QLQ CLL-16. Previously treated patients had longer disease duration (7 vs. 5 years), higher prevalence of serious comorbidities (45.5% vs. 36.2%) and high-risk molecular markers (unmutated IGHV 55.6% vs. 17.1%; TP53 mutation 15.2% vs. 4.0%). Health-related quality of life scores were similar between groups. In the DCE, W & W patients rated "possible occurrence of infections" highest (relative importance [RI] = 36.2%), followed by "treatment and relevant duration" (RI = 28.0%) and "progression-free survival (PFS)" (RI = 16.9%). Previously treated patients rated "treatment and relevant duration" highest (RI = 33.3%), followed by "possible occurrence of infections" (RI = 28.8%), "possible occurrence of organ damage" (RI = 19.4%), and "PFS" (RI = 9.8%). Concern over infection was rated highest overall; unexpectedly PFS was not among the most important criteria in either group, suggesting that the first COVID-19 pandemic wave may have influenced patient preferences and concerns about CLL therapy options

Efficacy of bendamustine and rituximab as first salvage treatment in chronic lymphocytic leukemia and indirect comparison with ibrutinib: A GIMEMA, ERIC and UK CLL FORUM study

We performed an observational study on the efficacy of bendamustine and rituximab (BR) as first salvage regimen in chronic lymphocytic leukemia (CLL). In an intention-to-treat analysis including 237 patients, the median progression-free survival (PFS) was 25 months. The presence of del (17p), unmutated IGHV and advanced stage were associated with a shorter PFS at multivariate analysis. The median time-to-next treatment was 31.3 months. Front-line treatment with a chemoimmunotherapy regimen was the only predictive factor for a shorter time to next treatment at multivariate analysis. The median overall survival (OS) was 74.5 months. Advanced disease stage (i.e. Rai stage III-IV or Binet stage C) and resistant disease were the only parameters significantly associated with a shorter OS. Grade 3-5 infections were recorded in 6.3% of patients. A matched-adjusted indirect comparison with ibrutinib given second-line within Named Patient Programs in the United Kingdom and in Italy was carried out with OS as objective end point. When restricting the analysis to patients with intact 17p who had received chemoimmunotherapy in first line, there was no difference in OS between patients treated with ibrutinib (63% alive at 36 months) and patients treated with BR (74.4% alive at 36 months). BR is an efficacious first salvage regimen in CLL in a real-life population, including the elderly and unfit patients. BR and ibrutinib may be equally effective in terms of OS when used as first salvage treatment in patients without 17p deletion. (Registered at clinicaltrials.gov identifier: 02491398)

Systematic versus on-demand early palliative care: results from a multicentre, randomised clinical trial

Background Early palliative care (EPC) in oncology has been shown to have a positive impact on clinical outcome, quality-of-care outcomes, and costs. However, the optimal way for activating EPC has yet to be defined. Methods This prospective, multicentre, randomised study was conducted on 207 outpatients with metastatic or locally advanced inoperable pancreatic cancer. Patients were randomised to receive ‘standard cancer care plus on-demand EPC’ (n = 100) or ‘standard cancer care plus systematic EPC’ (n = 107). Primary outcome was change in quality of life (QoL) evaluated through the Functional Assessment of Cancer Therapy – Hepatobiliary questionnaire between baseline (T0) and after 12 weeks (T1), in particular the integration of physical, functional, and Hepatic Cancer Subscale (HCS) combined in the Trial Outcome Index (TOI). Patient mood, survival, relatives' satisfaction with care, and indicators of aggressiveness of care were also evaluated. Findings The mean changes in TOI score and HCS score between T0 and T1 were −4.47 and −0.63, with a difference between groups of 3.83 (95% confidence interval [CI] 0.10–7.57) (p = 0.041), and −2.23 and 0.28 (difference between groups of 2.51, 95% CI 0.40–4.61, p = 0.013), in favour of interventional group. QoL scores at T1 of TOI scale and HCS were 84.4 versus 78.1 (p = 0.022) and 52.0 versus 48.2 (p = 0.008), respectively, for interventional and standard arm. Until February 2016, 143 (76.9%) of the 186 evaluable patients had died. There was no difference in overall survival between treatment arms. Interpretations Systematic EPC in advanced pancreatic cancer patients significantly improved QoL with respect to on-demand EPC