CAR-T therapy has transformed the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), particularly in pediatric and young adult patients. Many studies report one-year overall survival rates of between 60% and 80% following therapy. Event-free survival rates at one year are around 50–70%, with 40–50% of patients in remission after two years. Despite these impressive results, disease relapse remains a problem. Future CAR-T cell platforms should target multiple antigens, and the optimal design of such constructs must be determined. Modern trials should explore the role of CAR-T cell therapy as a consolidation treatment for patients with high-risk ALL, including those with persistent minimal residual disease at the end of induction/consolidation therapy, an IKZF1-positive gene expression profile, or a TP53 mutation or Ph-like gene expression profile. Improving the efficiency of gene-editing methods could lead to higher success rates in creating CAR-T cells, as well as reducing manufacturing time and costs. Producing universal CAR-T cells from healthy donors could significantly reduce production time and costs. These issues underscore the dynamic and evolving nature of B-ALL research. Ongoing studies and clinical trials are addressing many of these challenges in order to improve outcomes for B-ALL patients and expand the applications of CAR-T cell therapy.

Menin inhibitors are the first targeted therapies for KMT2A-rearranged and NPM1-mutated acute leukemias, addressing a significant unmet need in these high-risk subtypes. Revumenib received approval in 2024–2025 for relapsed or refractory KMT2A-rearranged acute leukemia and NPM1-mutated AML. The AUG-MENT-101 trial reported a 23% composite complete remission rate in heavily pretreated patients, with 61% of responders achieving MRD negativity. Several menin inhibitors, including ziftomenib, bleximenib, and enzomenib, are in clinical development. They demonstrate similar efficacy, but their safety profiles differ, especially regarding QTc prolongation and coverage of resistance mutations. Combination therapies with azacitidine and venetoclax or intensive chemotherapy have achieved high response rates in newly diagnosed patients, supporting their potential use in frontline treatment. Acquired resistance, often due to MEN1 mutations at the drug-binding interface, occurs in about 40% of cases. Distinct resistance patterns among menin inhibitors suggest the possibility of sequential therapy. Approximately 30–40% of responders in relapsed or refractory trials proceeded to allogeneic transplantation, which remains a key pathway to potential cure. This review examines the molecular mechanisms of the menin-KMT2A interaction, and summarizes clinical trial data on the efficacy and safety of menin inhibitors as monotherapy and in combination.

Background: This real-life study aimed to investigate the possible impact of D-VTd induction therapy on hematopoietic engraftment after autologous stem cell transplantation (auto-SCT). Methods: Sixty consecutive NDMM patients received four cycles of induction therapy with D-VTd. The conditioning regimen consisted of melphalan 200 mg/m². These patients were compared with a historical control group of 80 patients who received four cycles of VTd as induction therapy. Results: The median days to reach neutrophil and platelet engraftment significantly differed between patients treated with D-VTd (11 and 13 days, respectively) and VTd (10 and 12 days). Univariate Cox analyses show that patients treated with D-VTd had a hazard ratio of neutrophil engraftment that was 42% significantly lower than those in the VTd arm (HR: 0.58, p = 0.002), and a multivariate model confirmed this result. Patients treated with D-VTd developed FN more frequently. Univariate and multivariate logistic regressions revealed an association between D-VTd and FN. Delayed engraftment did not correlate with more extended hospitalization. No patients died in the first six months after transplantation. Conclusions: Our real-life study showed that a four-drug induction therapy containing DARA does not impact transplant safety outcomes.

Background/Objectives: Myelofibrosis (MF) is a clonal myeloproliferative neoplasm driven by dysregulated JAK-STAT signaling, characterized by progressive marrow fibrosis, splenomegaly, constitutional symptoms, and increased risk of leukemic transformation. Allogeneic hematopoietic stem cell transplantation (allo-HCT) remains the only potentially curative intervention. In Italy, allo-HCTs for myeloproliferative neoplasms (MPN, i.e., myelofibrosis, polycythaemia vera, and essential thrombocythaemia combined) increased by 163% from 2015 to 2025; MF-specific procedure counts were not separately available in this registry export, so this figure should not be read as MF-specific, with MPN accounting for 8% of all allogeneic procedures (n = 171) in 2025, showing a 29.5% year-on-year increase from 2024. Concurrently, the demographic profile shifted, with individuals aged 60 and over representing 38% of all recipients, surpassing other age groups for the first time in 2025. Results: This review synthesizes current evidence on transplant indications and timing, pre-transplant management, donor selection, and conditioning regimen optimization, emphasizing the emerging role of treosulfan-based and dual-alkylator platforms, including the thiotepa–treosulfan–fludarabine (TTF) regimen. Post-transplant molecular MRD monitoring and relapse management are also discussed. Three-year overall survival in myelofibrosis ranges from about 59% to 67%, depending on donor type, with outcomes improving due to better patient selection, optimized conditioning, and supportive care. Conclusions: Prospective randomized trials are urgently needed to validate optimal conditioning intensity, the role of novel JAK inhibitors in the peri-transplant period, and MRD-guided pre-emptive strategies.

Background: Chimeric antigen receptor T-cell (CAR-T) therapy has transformed the management of relapsed or refractory hematologic malignancies, achieving high response rates in B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, and multiple myeloma. While the efficacy of CAR-T therapy is well established, quality of life (QoL) metrics have become increasingly important for guiding treatment decisions, patient counseling, and survivorship planning. Objectives: Most patients undergoing CAR-T therapy recover their initial QoL within 3 months, an improvement not typically seen with other treatment options. A comprehensive understanding of QoL is essential for delivering patient-centered care in the evolving CAR-T landscape. Conclusions: This review synthesizes current evidence on QoL outcomes in CAR-T recipients, including acute effects, recovery trajectories, comparisons with conventional therapies, and strategies to optimize QoL.

Background: Systemic mastocytosis (SM) is a clonal mast cell (MC) neoplasm driven by somatically acquired activating mutations in the KIT receptor tyrosine kinase (CD117), resulting in pathological accumulation of morphologically atypical MCs in extracutaneous organs. The KIT D816V substitution is detectable in over 95% of cases by high-sensitivity next-generation sequencing (NGS) or allele-specific PCR. This gain-of-function variant confers ligand-independent receptor autophosphorylation, leading to constitutive activation of downstream signaling cascades that promote MC progenitor survival, clonal expansion, and resistance to apoptosis. Co-occurring somatic mutations in TET2, SRSF2, ASXL1, CBL, and RUNX1, increasingly identified in the context of clonal hematopoiesis of indeterminate potential, are associated with more aggressive phenotypes and independently confer adverse prognostic impact. Results: The 2022 WHO classification delineates indolent forms from advanced-phase SM, aggressive SM, SM with an associated hematologic neoplasm (SM-AHN), and MC leukemia, which produce progressive end-organ damage through both neoplastic tissue infiltration and uncontrolled mediator release. Formal diagnosis requires integration of histological criteria (multifocal bone marrow MC aggregates of ≥15 cells), immunophenotypic aberrancies (CD25, CD2, and/or CD30 coexpression on MCs by flow cytometry or immunohistochemistry), biochemical markers (baseline serum tryptase ≥ 20 ng/mL), and molecular confirmation of KIT D816V or equivalent pathogenic KIT mutation. The development of type I KIT inhibitors with selectivity for the D816V-mutant conformation has fundamentally restructured the therapeutic field of advanced SM. Conclusions: This review provides a thorough synthesis of SM pathobiology, WHO-defined diagnostic and classification criteria, validated prognostic tools, and the developing landscape of KIT-directed and combination therapies, with direct translational relevance for specialist practitioners managing this heterogeneous myeloid neoplasm.