Agostino Tafuri

Background/Objectives: Ibrutinib has significantly improved outcomes in chronic lymphocytic leukemia (CLL), but evidence from real-world settings on the impact of early dose modifications and consequent relative dose intensity (RDI) maintenance on survival outcomes is limited. This study evaluated the impact of dose reductions and RDI maintenance during the first 90 days of treatment on clinical outcomes in patients with CLL receiving ibrutinib in routine clinical practice. Methods: A post hoc analysis of the prospective observational EVIdeNCE study (NCT03720561) was conducted, including 275 patients with CLL treated with ibrutinib. Baseline clinical and biological factors associated with early dose modifications and RDI maintenance over the first 90 days were analyzed. Cox proportional hazards models, adjusted for disease- and patient-related covariates, were applied to assess associations with overall survival (OS) and progression-free survival (PFS), using a landmark approach to control for immortal time bias. Results: Patients with higher comorbidity burden—indicated by higher Cumulative Illness Rating Scale scores and poorer ECOG performance status—were more likely to undergo early dose reductions. RDI declined slightly over 90 days, but most patients maintained ≥80% of their RDI. The impact of disease-risk factors appeared more clearly when assessing the relationship between 100% RDI at 90 days and PFS, with ibrutinib at 100% RDI associated with improved PFS (hazard ratio, HR 2.26, 95% confidence interval, CI: 1.23–4.15). However, after adjusting for patient characteristics (e.g., comorbidity burden and cardiovascular history), the 100% RDI rate no longer showed a statistically significant effect on PFS (HR 1.84, 95% CI: 0.93–3.63). Conclusions: Baseline comorbidities and functional status drive early dose modifications, but these adjustments and RDI variability do not independently impact survival outcomes, confirming the overall tolerability of ibrutinib in real-world CLL management.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy, typically presenting with systemic symptoms and mediastinal involvement. Leukemia cutis (LC) and renal infiltration are rare, especially at disease onset. A 27-year-old man presented with a solitary scalp lesion without systemic symptoms or hematologic abnormalities. Histopathology revealed a blastoid lymphoid infiltrate with a T-ALL immunophenotype. Two weeks later, laboratory tests showed leukocytosis, lymphocytosis, and renal dysfunction. Imaging revealed a large mediastinal mass, scalp soft tissue involvement, and bilateral renal infiltration. Bone marrow biopsy confirmed T-ALL with a mature phenotype. FISH identified TRAD:NKX2 rearrangement and CDKN2AB deletion. The patient received three cycles of pediatric-inspired chemotherapy, achieving complete molecular remission and resolution of extramedullary disease. He subsequently underwent allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-matched sibling. Post-transplant complications included febrile neutropenia and mucositis. On day +100, he remained in minimal residual disease (MRD)-negative remission. This case illustrates a rare presentation of T-ALL with isolated skin involvement and renal infiltration at diagnosis, highlighting the importance of early biopsy and immunophenotyping of atypical skin lesions. Intensive chemotherapy followed by HSCT represents a viable strategy for young adults with high-risk T-ALL and extramedullary disease.

Langerhans cell sarcoma (LCS) is a rare and aggressive neoplasm characterized by a clonal proliferation of Langerhans cells (LCs), with multi-organ involvement and poor prognosis. Diagnostic challenges arise from its rarity and overlapping features with Langerhans cell histiocytosis (LCH), requiring immunophenotypic and histological analysis for differentiation. This case report discusses a 67-year-old male with multi-organ LCS involvement. Diagnosis was confirmed via liver biopsy and genetic analysis, revealing a MAP2K1 mutation. Treatment with subcutaneous cladribine and dexamethasone resulted in significant clinical and radiological improvement, despite hematological toxicity due to an underlying myelodysplastic neoplasm (MDS). This case proves the potential efficacy of cladribine for disseminated LCS and highlights the necessity for further research into optimal therapeutic approaches for this rare malignancy.

Introduction: Primary bone lymphoma (PBL) is a rare clinical entity, accounting for less than 5% of all extranodal non-Hodgkin lymphomas and approximately 5% of primary bone tumors. Diffuse large B-cell lymphoma (DLBCL) is the most common histotype, accounting for about 80% of all PBL cases. Conversely, the incidence of indolent primary bone lymphomas (iPBL) represents less than 1% of all reported PBL cases, and data on these rarer lymphomas are scarce. Drawing on diagnostic criteria developed by the World Health Organization (WHO) and the International Extranodal Lymphoma Study Group (IELSG), we report a rare case of primary bone follicular lymphoma, focusing specifically on the clinical presentation and treatment. Discussion: Additionally, we provide a systematic review of the literature data on this very rare lymphoproliferative entity.

Multiple Myeloma is a hematological neoplasm that, over the recent few years, has benefited from numerous therapeutic options. Among the latter, CAR-T stands out as the most recent and one of the most promising treatments currently available. Despite its recent introduction, multiple CAR-T products have already been approved, and research regarding cellular therapy is rapidly increasing. We conducted a comprehensive search and review of the available literature, including published studies and abstracts from recent meetings (ASH, ASCO, ASTCT, IMS), regarding Multiple Myeloma and CAR-T therapy. We describe the discovery and research regarding promising targets like the B-Cell Maturation Antigen (BCMA) and others, the origin and nature of CAR-T cells, and the recent introduction of anti-BCMA CAR-Ts Idecabtagene-vicleucel and Ciltacabtagene-autoleucel, which are currently the only approved CAR-T products for MM. Additionally, we discuss non-BCMA-targeting CAR-Ts and their clinical implications. Given the significant impact of cellular therapy, we provide an overview of its limitations and possible adverse implications, as well as related resistance mechanisms. Finally, we describe the current research aimed at improving CAR-T therapy in MM, including structural innovations and new therapeutic approaches, such as in the earlier lines of treatment and maintenance therapy.

Chronic Lymphocytic Leukemia (CLL) is an indolent malignancy characterized by the accumulation of quiescent mature B cells. However, these cells are transcriptionally and translationally active, implicating an active metabolism. The recent literature suggests that CLL cells have an oxidative-type phenotype. Given the role of cell metabolism, which is able to influence the outcome of treatments, in other neoplasms, we aimed to assess its prognostic role in CLL patients by determining the ex vivo bioenergetic metabolic profile of CLL cells, evaluating the correlation with the patient clinical/biological characteristics and the in vivo response to BTK inhibitor treatment. Clustering analysis of primary samples identified two groups, characterized by low (CLL low) or high (CLL high) bioenergetic metabolic rates. Compared to the CLL high, CLL with lower bioenergetic metabolic rates belonged to patients characterized by a statistically significant higher white blood cell count and by unfavorable molecular genetics. More importantly, patients in the CLL low cluster displayed a better and more durable response to the BTK inhibitor ibrutinib, thus defining a bioenergetic metabolic subgroup that can benefit the most from this therapy.

Real-world data in clinical practice are needed to confirm the efficacy and safety that ibrutinib has demonstrated in clinical trials of patients with chronic lymphocytic leukemia (CLL). We described the real-world persistence rate, patterns of use, and clinical outcomes in 309 patients with CLL receiving single-agent ibrutinib in first line (1L, n = 118), 2L (n = 127) and ≥3L (n = 64) in the prospective, real-world, Italian EVIdeNCE study. After a median follow-up of 23.9 months, 29.8% of patients discontinued ibrutinib (1L: 24.6%, 2L: 29.9%, ≥3L: 39.1%), mainly owing to adverse events (AEs)/toxicity (14.2%). The most common AEs leading to discontinuation were infections (1L, ≥3L) and cardiac events (2L). The 2-year retention rate was 70.2% in the whole cohort (1L: 75.4%, 2L: 70.1%, ≥3L: 60.9%). The 2-year PFS and OS were, respectively, 85.4% and 91.7% in 1L, 80.0% and 86.2% in 2L, and 70.1% and 80.0% in ≥3L. Cardiovascular conditions did not impact patients’ clinical outcomes. The most common AEs were infections (30.7%), bleeding (12.9%), fatigue (10.0%), and neutropenia (9.7%), while grade 3–4 atrial fibrillation occurred in 3.9% of patients. No new safety signals were detected. These results strongly support ibrutinib as a valuable treatment option for CLL.

Oxidative stress and impaired mitophagy are the hallmarks of cardiomyocyte senescence. Specifically, a decrease in mitophagic flux leads to the accumulation of damaged mitochondria and the development of senescence through increased ROS and other mediators. In this study, we describe the preventive role of A5⁺, a mix of polyphenols and other micronutrients, in doxorubicin (DOXO)-induced senescence of H9C2 cells. Specifically, H9C2 cells exposed to DOXO showed an increase in the protein expression proteins of senescence-associated genes, p21 and p16, and a decrease in the telomere binding factors TRF1 and TRF2, indicative of senescence induction. Nevertheless, A5⁺ pre-treatment attenuated the senescent-like cell phenotype, as evidenced by inhibition of all senescent markers and a decrease in SA-β-gal staining in DOXO-treated H9C2 cells. Importantly, A5⁺ restored the LC3 II/LC3 I ratio, Parkin and BNIP3 expression, therefore rescuing mitophagy, and decreased ROS production. Further, A5⁺ pre-treatment determined a ripolarization of the mitochondrial membrane and improved basal respiration. A5⁺-mediated protective effects might be related to its ability to activate mitochondrial SIRT3 in synergy with other micronutrients, but in contrast with SIRT4 activation. Accordingly, SIRT4 knockdown in H9C2 cells further increased MnSOD activity, enhanced mitophagy, and reduced ROS generation following A5⁺ pre-treatment and DOXO exposure compared to WT cells. Indeed, we demonstrated that A5⁺ protects H9C2 cells from DOXO-induced senescence, establishing a new specific role for A5⁺ in controlling mitochondrial quality control by restoring SIRT3 activity and mitophagy, which provided a molecular basis for the development of therapeutic strategies against cardiomyocyte senescence.