BTK (Bruton’s tyrosine kinase) has become a key therapeutic target across several hematologic diseases, beginning with its original use in CLL/SLL. As a central mediator of B-cell receptor signaling and microenvironment interactions, BTK supports survival, proliferation, and trafficking in multiple mature B-cell malignancies (mantle cell lymphoma, marginal zone lymphoma, Waldenström macroglobulinemia, and other indolent/aggressive lymphomas) and in selected immune-mediated conditions such as chronic graft-versus-host disease. Covalent BTK inhibitors (ibrutinib, acalabrutinib, and zanubrutinib) irreversibly bind the C481 residue and have produced high response rates and durable disease control, often replacing chemoimmunotherapy in the relapsed setting and, for some entities, even in the first line. Differences in kinase selectivity lead to different safety profiles: second-generation covalent agents generally maintain efficacy while reducing significant off-target toxicities, especially atrial fibrillation and hypertension. Resistance to covalent BTK inhibitors most commonly develops through BTK C481 substitutions and activating PLCG2 mutations, with other kinase-domain variants increasingly recognized. Non-covalent BTK inhibitors (e.g., pirtobrutinib) bind BTK independently of C481, can overcome classic C481-mediated resistance, and extend BTK pathway targeting into later lines of therapy. Overall, BTK inhibition has evolved into a versatile platform enabling long-term, often chemo-free management strategies.

Background/Objectives: Acute myeloid leukemia (AML) with FLT3 internal tandem duplication (FLT3-ITD) mutations carries a poor prognosis. While FLT3 inhibitors like midostaurin show benefits in combination with chemotherapy, the role of allelic ratio (AR), NPM1 mutation status, and hematopoietic stem cell transplantation (HSCT) remains uncertain. Real-world data can help refine prognostic classification and treatment strategies. Methods: We retrospectively analyzed 37 fit patients with FLT3-ITD AML treated with standard “7+3” chemotherapy, with and without midostaurin, between 2013 and 2022. Patients were stratified by FLT3-ITD AR, NPM1 status, and treatment approach. Outcomes assessed included complete remission (CR), disease-free survival (DFS), and overall survival (OS). Results: Overall, 67.6% achieved CR/CRi. Response rates did not differ significantly by AR (low vs. high: 66.7% vs. 69.2%) or midostaurin use (72.6% vs. 60%; p = 0.49). NPM1 mutations were associated with improved DFS (10.3 vs. 3 months, p = 0.036) but not OS. HSCT, performed in 54.1% of patients, mainly in first remission (CR1), significantly prolonged DFS (not reached vs. 5.3 months, p = 0.005) and remained an independent predictor in multivariate analysis (HR: 0.160, p = 0.039). OS (median 15.1 months) did not vary significantly across subgroups. Among patients achieving CR1, OS was significantly longer in those who underwent HSCT after midostaurin-based induction compared to those not transplanted (median OS not reached vs. 12.8 months; 95% CI, 6.9–18.7; p = 0.045), whereas no significant benefit was observed after standard induction. In a landmark analysis restricted to patients transplanted in CR1, those who had received midostaurin-based induction showed a trend toward improved OS compared to those treated with standard induction (median OS not reached vs. 11.5 months; 95% CI, 0.5–25.0; p = 0.086). Conclusions: This real-life study supports the importance of NPM1 mutations and HSCT in CR1, especially in the midostaurin era, for improving DFS in FLT3-ITD AML. These findings support updated guidelines for reducing the prognostic weight of AR and highlight the need for improved post-remission strategies in this setting.

After European Medicines Agency (EMA) approval, national pricing and reimbursement procedures are necessary to guarantee access to drugs, based on the willingness to pay and the recognition of therapeutic value. These can result in delays in drug availability for patients, even for those with important unfmet needs for whom it may be necessary and ethical to ensure access. The objective of this study was to evaluate the use of ruxolitinib for patients with graft-versus-host disease (GvHD) after EMA approval at the University Hospital of Catania. We analysed data about the use of ruxolitinib in patients with GvHD, describing their basic characteristics, their outcomes and the cost of the treatment. In the reference period, 24 ruxolitinib treatments were started according to the Summary of Product Characteristic. The average treatment duration was 10 months. Twenty patients showed a response, maintained over time, with no adverse reactions. The total expenditure amounts to EUR 963,424. The use of ruxolitinib in a real population confirms its role in an important therapeutic need. The quantification of costs requires a reflection on the sustainability of early access to medicines authorised by the EMA for serious diseases and in the absence of therapeutic alternatives.

Background/Objectives: The combination of venetoclax (VEN) and hypomethylating agents (HMA), such as azacitidine (AZA) or decitabine (DEC), has transformed the treatment landscape for acute myeloid leukemia (AML) in patients unfit for intensive chemotherapy. However, optimal management of neutropenia and the impact of post-remission treatment interruptions (washouts) remain unclear. This study aimed to evaluate the safety and efficacy of post-remission washouts and their effect on clinical outcomes. Methods: We conducted a retrospective single-center study of 44 AML patients treated with HMA/VEN between 2020 and 2021. Clinical, molecular, and treatment-related data were collected, including treatment duration, post-remission washout duration, response rates, disease-free survival (DFS), and overall survival (OS). Statistical analyses included Fisher’s exact test and univariate and multivariate Cox models. Results: Overall, 61% of patients responded to therapy, with significantly higher response rates among those potentially eligible for the VIALE-A trial (86% vs. 39%, p = 0.002). Neither treatment duration nor post-remission washout length was associated with DFS or OS. DFS was significantly longer in patients treated with AZA compared to DEC (p = 0.006). Median OS was 7.7 months, with longer OS observed in patients who met VIALE-A trial eligibility criteria (p = 0.021). Achieving complete remission (CR) was associated with improved OS (14.5 months). Conclusions: Post-remission treatment interruptions (washouts) did not negatively impact DFS or OS, suggesting they may be a safe strategy to support hematologic recovery. However, the choice of HMA appears to influence response duration, with AZA outperforming DEC in maintaining disease control.

Background: Relapsed/refractory acute myeloid leukemia (R/R AML) remains a therapeutic challenge due to disease heterogeneity, resistance mechanisms, and poor tolerability to intensive regimens. Venetoclax (VEN), a BCL-2 inhibitor, has shown promise in combination with hypomethylating agents (HMAs), but data on response timing in the R/R setting are limited. The aim of this study was to assess the efficacy, safety, and kinetics of response to HMA-VEN therapy in a real-world cohort of R/R AML patients, with particular focus on early versus late responders. Methods: This prospective single-center study included 33 adult patients with R/R AML treated with VEN plus either azacitidine (AZA) or decitabine (DEC) from 2018 to 2021. The primary endpoint was the composite complete remission (cCR) rate and the rate of early and late response, respectively, occurring within two cycles of therapy or later; secondary endpoints included overall survival (OS), relapse-free survival (RFS), time to relapse (TTR), and safety. Results: The cCR was 58%, with complete remission (CR) or CR with incomplete recovery (CRi) achieved in 52% of patients. Median OS was 9 months. No significant differences in OS or TTR were observed between early (≤2 cycles) and late (>2 cycles) responders. Eight responders (42%) underwent allogeneic hematopoietic stem cell transplantation (HSCT), with comparable transplant rates in both groups of responders. Toxicity was manageable. Grade 3–4 neutropenia occurred in all patients, and febrile neutropenia occurred in 44% of patients. An Eastern Cooperative Oncology Group (ECOG) score >2 was associated with inferior response and shorter treatment duration. Conclusions: HMA-VEN therapy is effective and safe in R/R AML, including for patients with delayed responses. The absence of a prognostic disadvantage for late responders supports flexible treatment schedules and suggests that the continuation of therapy may be beneficial even without early blast clearance. Tailored approaches based on performance status and comorbidities are warranted, and future studies should incorporate minimal residual disease (MRD)-based monitoring to refine response assessment.