Proteasome Inhibitors Induce Apoptosis in Ex Vivo Cells of T-Cell Prolymphocytic Leukemia.

Finding an effective treatment for T-PLL patients remains a significant challenge. Alemtuzumab, currently the gold standard, is insufficient in managing the aggressiveness of the disease in the long term. Consequently, numerous efforts are underway to address this unmet clinical need.

Leukemic cell-secreted interleukin-9 suppresses cytotoxic T cell-mediated killing in chronic lymphocytic leukemia.

The tumor microenvironment (TME) plays a central role in the pathogenesis of chronic lymphocytic leukemia (CLL), contributing to disease progression and chemoresistance. Leukemic cells shape the TME into a pro-survival and immunosuppressive niche through contact-dependent and contact-independent interactions with the cellular components of the TME. Immune synapse (IS) formation is defective in CLL.

Chest pain in cardiac amyloidosis: occurrence, causes and prognostic significance.

Background: Chest pain is experienced by patients with cardiac amyloidosis (CA), but a systematic investigation of its frequency, underlying etiologies and clinical significance is lacking.

Methods: Clinical, echocardiographic, laboratory characteristics, available coronary arteries imaging and endomyocardial biopsy (EMB) findings of 174 patients with CA (n = 104 with transthyretin, ATTR; n = 70 with light chains, AL) were analyzed.

Results: Chest pain was reported in 66 (38%) CA patients.

Pro-inflammatory cells sustain leukemic clonal expansion in T-cell large granular lymphocyte leukemia.

T-cell large granular lymphocyte leukemia (T-LGLL) is a chronic lymphoproliferative disorder characterized by the clonal expansion of T-cell large granular lymphocytes (T-LGL). Immunophenotypic and genotypic features contribute to discriminate symptomatic (CD8+ STAT3-mutated T-LGLL) from clinically indolent patients, this latter group including CD8+ wildtype (wt), CD4+ STAT5B-mutated and wt cases. T-LGL lymphoproliferation is sustained both by somatic gain-offunction mutations (i.

Light-chain cardiac amyloidosis for the non-expert: pearls and pitfalls.

Cardiac amyloidosis (CA) is an uncommon, progressive, and fatal disease; the two main forms that can affect the heart are transthyretin CA and light chain CA (AL-CA). AL-CA is a medical urgency for which a diagnostic delay can be catastrophic for patients' outcome. In this manuscript, we focus on the pearls and pitfalls that are relevant to achieve a correct diagnosis and to avoid diagnostic and therapeutical delays.

Real-World Use and Effectiveness of Carfilzomib Plus Dexamethasone in Relapsed/Refractory Multiple Myeloma in Europe.

This prospective, observational study examined the real-world use of carfilzomib across 11 European countries in adults with relapsed/refractory multiple myeloma (RRMM) who received at least one prior line of therapy. Carfilzomib and dexamethasone (Kd) use, effectiveness and safety were analyzed. In total, 271 patients received Kd among 701 adults enrolled.

Lenalidomide-based triplet regimens in first relapsed multiple myeloma patients: real-world evidence from a propensity score matched analysis.

Lenalidomide and dexamethasone (Rd)-based triplets, in particular carfilzomib-Rd (KRd) and daratumumab-Rd (DaraRd), represent a standard of care in lenalidomide-sensitive multiple myeloma (MM) patients in first relapse. Meta-analysis of randomized clinical trials (RCT), suggested better outcome with DaraRd. Trying to address this issue in clinical practice, we collected data of 430 consecutive MM patients addressed to Rd-based triplets in first relapse between January 2017 and March 2021.

CK1α/RUNX2 Axis in the Bone Marrow Microenvironment: A Novel Therapeutic Target in Multiple Myeloma.

Multiple myeloma (MM) is a malignant plasma cell (PC) neoplasm, which also displays pathological bone involvement. Clonal expansion of MM cells in the bone marrow causes a perturbation of bone homeostasis that culminates in MM-associated bone disease (MMABD). We previously demonstrated that the S/T kinase CK1α sustains MM cell survival through the activation of AKT and β-catenin signaling.

Defining TCRγδ lymphoproliferative disorders by combined immunophenotypic and molecular evaluation.

Tγδ large granular lymphocyte leukemia (Tγδ LGLL) is a rare lymphoproliferative disease, scantily described in literature. A deep-analysis, in an initial cohort of 9 Tγδ LGLL compared to 23 healthy controls, shows that Tγδ LGLL dominant clonotypes are mainly public and exhibit different V-(D)-J γ/δ usage between patients with symptomatic and indolent Tγδ neoplasm. Moreover, some clonotypes share the same rearranged sequence.

Single-cell characterization of leukemic and non-leukemic immune repertoires in CD8 T-cell large granular lymphocytic leukemia.

T cell large granular lymphocytic leukemia (T-LGLL) is a rare lymphoproliferative disorder of mature, clonally expanded T cells, where somatic-activating STAT3 mutations are common. Although T-LGLL has been described as a chronic T cell response to an antigen, the function of the non-leukemic immune system in this response is largely uncharacterized. Here, by utilizing single-cell RNA and T cell receptor profiling (scRNA+TCRαβ-seq), we show that irrespective of STAT3 mutation status, T-LGLL clonotypes are more cytotoxic and exhausted than healthy reactive clonotypes.

Identification of novel STAT5B mutations and characterization of TCRβ signatures in CD4+ T-cell large granular lymphocyte leukemia.

CD4+ T-cell large granular lymphocyte leukemia (T-LGLL) is a rare subtype of T-LGLL with unknown etiology. In this study, we molecularly characterized a cohort of patients (n = 35) by studying their T-cell receptor (TCR) repertoire and the presence of somatic STAT5B mutations. In addition to the previously described gain-of-function mutations (N642H, Y665F, Q706L, S715F), we discovered six novel STAT5B mutations (Q220H, E433K, T628S, P658R, P702A, and V712E).

Pharmacological modulation of Kv1.3 potassium channel selectively triggers pathological B lymphocyte apoptosis in vivo in a genetic CLL model.

Background: Ion channels are emerging as promising oncological targets. The potassium channels Kv1.3 and IKCa are highly expressed in the plasma membrane and mitochondria of human chronic lymphocytic leukemia (CLL) cells, compared to healthy lymphocytes.

The long non-coding RNA overexpression impacts on acute myeloid leukemia differentiation and mitochondrial dynamics.

Patients with acute myeloid leukemia (AML) carrying high-risk genetic lesions or high residual disease levels after therapy are particularly exposed to the risk of relapse. Here, we identified the long non-coding RNA able to cluster an AML subgroup with peculiar gene signatures linked to hematopoietic cell differentiation and mitochondrial dynamics. silencing triggered hematopoietic commitment in healthy CD34+ cells, whereas in AML cells the pathological undifferentiated state was rescued.

Targeting of HSP70/HSF1 Axis Abrogates In Vitro Ibrutinib-Resistance in Chronic Lymphocytic Leukemia.

The Btk inhibitor ibrutinib has significantly changed the management of chronic lymphocytic leukemia (CLL) patients. Despite its clinical efficacy, relapses occur, and outcomes after ibrutinib failure are poor. Although BTK and PLCγ2 mutations have been found to be associated with ibrutinib resistance in a fair percentage of CLL patients, no information on resistance mechanisms is available in patients lacking these mutations.

Dealing With High-Risk AL Amyloidosis Patients: A Single Hematologic Center Experience.

Purpose: To assess the feasibility and the results of Bortezomib-based treatment of "high-risk" AL-amyloidosis patients in a hematology ward.

Methods: We report on 52 high-risk amyloidosis patients treated with first-line bortezomib-based chemotherapy.

Results: At day 30 from the beginning of the therapy, 23 patients (44%) achieved a hematological response (complete response plus very good partial response); 14 patients (27%) achieved a partial response; 15 patients (29%) were non-responders.

Overall survival of myelodysplastic syndrome patients after azacitidine discontinuation and applicability of the North American MDS Consortium scoring system in clinical practice.

Background: Azacitidine (AZA) is the standard treatment for myelodysplastic syndromes (MDS); however, many patients prematurely stop therapy and have a dismal outcome.

Methods: The authors analyzed outcomes after AZA treatment for 402 MDS patients consecutively enrolled in the Italian MDS Registry of the Fondazione Italiana Sindromi Mielodisplastiche, and they evaluated the North American MDS Consortium scoring system in a clinical practice setting.

Results: At treatment discontinuation, 20.

Lack of Viral Load Within Chronic Lymphoproliferative Disorder of Natural Killer Cells: What Is Outside the Leukemic Clone?

Large granular lymphocyte leukemias (LGLL) are sustained by proliferating cytotoxic T cells or NK cells, as happens in Chronic Lymphoproliferative Disorder of Natural Killer cells (CLPD-NK), whose etiology is only partly understood. Different hypotheses have been proposed on the original events triggering NK cell hyperactivation and transformation, including a role of viral agents. In this perspective, we revise the lines of evidence that suggested a pathogenetic role in LGLL of the exposure to retroviruses and that identified Epstein Barr Virus (EBV) in other NK cell leukemias and lymphomas and focus on the contrasting data about the importance of viral agents in CLPD-NK.

Comparison of ibrutinib and idelalisib plus rituximab in real-life relapsed/resistant chronic lymphocytic leukemia cases.

Objectives: To compare the capacity of ibrutinib (IB) and idelalisib-rituximab (IDELA-R) of prolonging overall survival (OS) as in CLL patients, previously treated with chemotherapy only.

Methods: A real-life cohort of 675 cases has been identified and investigated in the database of the groups participating in the study.

Results: At an unadjusted univariate analysis, a significant death risk reduction was observed favoring IB (IDELA-R vs IB HR = 0.

Enhanced IL-9 secretion by p66Shc-deficient CLL cells modulates the chemokine landscape of the stromal microenvironment.

The stromal microenvironment is central to chronic lymphocytic leukemia (CLL) pathogenesis. How leukemic cells condition the stroma to enhance its chemoattractant properties remains elusive. Here, we show that mouse and human CLL cells promote the contact-independent stromal expression of homing chemokines.