Efficacy and safety of venetoclax plus hypomethylating agents in relapsed/refractory acute myeloid leukemia: a multicenter real-life experience

Venetoclax (VEN) has been shown to play a synergistic effect in combination with hypomethylating agents (HMAs) in the frontline treatment of acute myeloid leukemia (AML). However, the potential role of this therapy in the relapsed/refractory (R/R) AML setting, still needs to be further unveiled. The aim of the current study was to retrospectively outline the safety profile, response and survival outcomes of R/R AML patients treated with VEN in association with HMAs. Clinical, biological, and molecular data were collected from 57 patients with R/R AML treated with VEN combined with azacitidine or decitabine between 2018 and 2023. The median age of patients was 63 years, 38 (66.7%) received treatment for relapsed disease while 19 (33.3%) for refractory disease, 5 (8.7%) were treated for molecular relapse. A consistent proportion of the cohort was represented by patients with unfavorable prognostic factors such as complex karyotype (36.8%), secondary AML (29.8%), previous exposure to HMAs (38.6%), and relapse after allogeneic stem cell transplant (22.8%). A total of 14 patients achieved CR (24.6%), 3 (5.3%) CRi, 3 (5.3%) MLFS, and 3 (5.3%) PR, accounting for an ORR of 40.4%. The CR/CRi rate was higher in the group treated with azacitidine than in the group treated with decitabine (37.8% vs. 15%). The median OS was 8.2 months, reaching 20.1 months among responding patients. VEN-HMAs treatment allowed to bridge to allogeneic stem cell transplantation 11 (23.9%) of eligible patients, for which a median OS of 19.8 months was shown. On multivariate analysis, ECOG performance status ≥2, complex karyotype and not proceeding to allogeneic stem cell transplantation after therapy with VEN-HMAs were the factors independently associated with shorter OS. Patients treated with the azacitidine rather than the decitabine containing regimen generally displayed a trend toward superior outcomes. The major toxicities were prolonged neutropenia and infections. In conclusion, this study showed how VEN-HMAs could represent an effective salvage therapy in patients with R/R AML, even among some of those patients harboring dismal prognostic features, with a good toxicity profile. Further prospective studies are thus warranted

Chronic Lymphocytic Leukemia B Cells Can Undergo Somatic Hypermutation and Intraclonal Immunoglobulin VHDJH Gene Diversification

Chronic lymphocytic leukemia (CLL) arises from the clonal expansion of a CD5+ B lymphocyte that is thought not to undergo intraclonal diversification. Using VHDJH cDNA single strand conformation polymorphism analyses, we detected intraclonal mobility variants in 11 of 18 CLL cases. cDNA sequence analyses indicated that these variants represented unique point-mutations (1–35/patient). In nine cases, these mutations were unique to individual submembers of the CLL clone, although in two cases they occurred in a large percentage of the clonal submembers and genealogical trees could be identified. The diversification process responsible for these changes led to single nucleotide changes that favored transitions over transversions, but did not target A nucleotides and did not have the replacement/silent nucleotide change characteristics of antigen-selected B cells. Intraclonal diversification did not correlate with the original mutational load of an individual CLL case in that diversification was as frequent in CLL cells with little or no somatic mutations as in those with considerable mutations. Finally, CLL B cells that did not exhibit intraclonal diversification in vivo could be induced to mutate their VHDJH genes in vitro after stimulation. These data indicate that a somatic mutation mechanism remains functional in CLL cells and could play a role in the evolution of the clone

GSK-3 Inhibition Modulates Metalloproteases in a Model of Lung Inflammation and Fibrosis

Idiopathic pulmonary fibrosis (IPF) is mainly characterized by aberrant extracellular matrix deposition, consequent to epithelial lung injury and myofibroblast activation, and inflammatory response. Glycogen synthase kinase 3 (GSK-3) is a serine–threonine kinase involved in several pathways, and its inhibition has been already suggested as a therapeutic strategy for IPF patients. There is evidence that GSK-3 is able to induce matrix metalloproteinase (MMP) expression and that its inhibition modulates MMP expression in the tissues. The aim of our study was to investigate the role of GSK-3 and its inhibition in the modulation of MMP-9 and -2 in an in vivo mouse model of lung fibrosis and in vitro using different cell lines exposed to pro-inflammatory or pro-fibrotic stimuli. We found that GSK-3 inhibition down-modulates gene expression and protein levels of MMP-9, MMP-2, and their inhibitors TIMP-1 and TIMP-2 in inflammatory cells harvested from bronchoalveolar lavage fluid (BALF) of mice treated with bleomycin as well as in interstitial alveolar macrophages and cuboidalized epithelial alveolar cells. To the same extent, GSK-3 inhibition blunted the increased MMP-9 and MMP-2 activity induced by pro-fibrotic stimuli in a human lung fibroblast cell line. Moreover, the αSMA protein level, a marker of fibroblast-to-myofibroblast transition involved in fibrosis, was decreased in primary fibroblasts treated with TGFβ following GSK-3 inhibition. Our results confirm the implication of GSK-3 in lung inflammation and fibrosis, suggesting that it might play its role by modulating MMP expression and activity but also pushing fibroblasts toward a myofibroblast phenotype and therefore enhancing extracellular matrix deposition. Thus, its inhibition could represent a possible therapeutic strategy

Glycogen Synthase Kinase-3 regulates multiple myeloma cell growth and bortezomib-induced cell death

BACKGROUND: Glycogen Synthase Kinase-3 (GSK-3) \u3b1 and \u3b2 are two serine-threonine kinases controlling insulin, Wnt/\u3b2-catenin, NF-\u3baB signaling and other cancer-associated transduction pathways. Recent evidence suggests that GSK-3 could function as growth-promoting kinases, especially in malignant cells. In this study, we have investigated GSK-3\u3b1 and GSK-3\u3b2 function in multiple myeloma (MM). METHODS: GSK-3 \u3b1 and \u3b2 expression and cellular localization were investigated by Western blot (WB) and immunofluorescence analysis in a panel of MM cell lines and in freshly isolated plasma cells from patients. MM cell growth, viability and sensitivity to bortezomib was assessed upon treatment with GSK-3 specific inhibitors or transfection with siRNAs against GSK-3 \u3b1 and \u3b2 isoforms. Survival signaling pathways were studied with WB analysis. RESULTS: GSK-3\u3b1 and GSK-3\u3b2 were differently expressed and phosphorylated in MM cells. Inhibition of GSK-3 with the ATP-competitive, small chemical compounds SB216763 and SB415286 caused MM cell growth arrest and apoptosis through the activation of the intrinsic pathway. Importantly, the two inhibitors augmented the bortezomib-induced MM cell cytotoxicity. RNA interference experiments showed that the two GSK-3 isoforms have distinct roles: GSK-3\u3b2 knock down decreased MM cell viability, while GSK-3\u3b1 knock down was associated with a higher rate of bortezomib-induced cytotoxicity. GSK-3 inhibition caused accumulation of \u3b2-catenin and nuclear phospho-ERK1, 2. Moreover, GSK-3 inhibition and GSK-3\u3b1 knockdown enhanced bortezomib-induced AKT and MCL-1 protein degradation. Interestingly, bortezomib caused a reduction of GSK-3 serine phosphorylation and its nuclear accumulation with a mechanism that resulted partly dependent on GSK-3 itself. CONCLUSIONS: These data suggest that in MM cells GSK-3\u3b1 and \u3b2 i) play distinct roles in cell survival and ii) modulate the sensitivity to proteasome inhibitors

Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study

Several small studies on patients with COVID-19 and haematological malignancies are available showing a high mortality in this population. The Italian Hematology Alliance on COVID-19 aimed to collect data from adult patients with haematological malignancies who required hospitalisation for COVID-19

Limbic Encephalitis with HU-Antibodies in T-cell Anaplastic Lymphoma. A Case Report

Limbic encephalitis is a rare paraneoplastic neurological syndrome usually associated with small cell lung cancers, testicular and breast cancers or B-cell lymphomas. We herein report the first patients with paraneoplastic limbic encephalitis associated with HU antibodies and anaplastic T-cell lymphoma

What’s New in the Classification, Diagnosis and Therapy of Myeloid Leukemias

Myeloid leukemias are a broad group of hematological disorders, characterized by heterogeneous clinical and biological features. In recent years, unprecedented genetic discoveries and clinical–biological correlations have revolutionized the field of myeloid leukemias. The most relevant changes have specifically occurred in acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), chronic myeloid leukemia (CML) and myeloid neoplasms (MNs) with eosinophilia. The recently published International Consensus Classification (ICC) of myeloid neoplasms has addressed these changes, providing an updated framework and revised diagnostic criteria for such entities. This is also the aim of the 5th edition of the WHO classification of hematopoietic tumors, whose preliminary version was published in 2022. Parallel to this, new therapeutic options and novel molecular targets have changed the management of many myeloid entities, including AML and CML. This review aims to address the most relevant updates in the classification and diagnosis of AML, CMML, CML and MNs with eosinophilia. The state of the art of treatment and future therapeutic options for such disorders are also discussed

Intramural hematoma of the esophagus in a woman with chronic renal failure and prophylactic heparin therapy

CASE REPORT An 86 year-old woman experienced chest pain, dyspnea, and dysphagia two days following orthopaedic surgery for a bimalleolus fracture of the right ankle. The patient was on prophylactic low weight molecular heparin and was affected by chronic renal failure. The chest computed tomography (CT) ruled out a pulmonary embolism but showed an intramural esophageal mass involving the entire esophagus. The lesion exhibited a blood like CT attenuation content that did not enhance after contrast administration. The esophagogram with gastrografin did not reveal filling defects nor communications between lumen and mucosa. Magnetic resonance confirmed CT results and excluded an aortic dissection. All radiological findings were suggestive of intramural hematoma of the esophagus. DISCUSSION AND CONCLUSIONS Intramural hematoma of the esophagus (IHE) is part of the spectrum of esophageal injuries that includes Mallory-Weiss tear and Boerhaave’s syndrome. IHE is the result of a hemorrhage within the submucosal layer. Predisposing conditions are abnormal hemostasis, traumatic events, aortic diseases. It can also occur spontaneously (idiopathic). Treatment should be conservative and includes risk factors withdrawal. The hematoma usually resolves in 1 to 3 weeks

Effects of N-acetyl-L-cysteine in patients with chronic atrophic gastritis and nonulcer dyspepsia: A phase III pilot study

Several studies have suggested that oxidative damage may contribute to gastritis. This damage is counteracted by various scavengers including glutathione (GSH), which may help defend the gastric mucosa. N-acetyl-L-cysteine (NAC), a GSH precursor, could thus be of therapeutic interest. This multiple-dose, double-masked, randomized, parallel-group, phase III pilot study was designed to assess the effects of NAC in 18 patients undergoing upper gastrointestinal endoscopy for dyspepsia who had endoscopically and histologically confirmed chronic atrophic gastritis but no peptic ulcer. Patients were randomly allocated to one of three treatment groups (NAC 1 g/d at bedtime, 1 g two times a day [2 g/d], or 2 g two times a day [4 g/d]) for 4 weeks. After treatment, patients underwent a second endoscopy. During both endoscopies, multiple biopsies were taken for histologic examination (based on a semiquantitative score according to the Sydney system). Reduced/oxidized glutathione (GSH/GSSG) and malondialdehyde (MDA) were also measured (using high-performance liquid chromatography and fluorometric assay). At recruitment, 6 patients tested negative and 12 tested positive for Helicobacter pylori. Serologic findings and symptoms (semi-quantitatively scored) were collected at the beginning and end of the trial. After treatment, 13 (72%) of 18 patients showed improvement on endoscopy, irrespective of NAC dose, and 5 (28%) showed no change. Histologically, polymorph infiltration was significantly reduced in patients who received 2 g of NAC. The 5-point total symptom score was lower, but not significantly so, in patients who received the other doses. Because of a high variability, no significant change in GSH and MDA was found. No difference was observed between H pylori-positive and -negative patients. No relevant changes were detected in laboratory findings, and the most common adverse events were constipation, abdominal pain, and flatulence. Our findings suggest that in patients with gastritis and nonulcer dyspepsia, NAC is fairly well tolerated and apparently leads to endoscopic, symptomatic, and to some extent histologic improvement, unrelated to changes in mucosal GSH levels