Monoclonal protein is frequently tested in marginal zone lymphoma, but interpretation is often inconsistent in practice because prior studies used selective testing and rarely linked serologic findings to biology or post-treatment dynamics. We analyzed 235 adults with newly diagnosed MZL receiving first-line systemic therapy at a single center (2010-2025). All patients had baseline serum protein electrophoresis, immunofixation, and free light chain testing. Plasmacytic differentiation was reviewed by hematopathologists. M-protein response (IMWG criteria) was assessed in patients with post-treatment data. The primary endpoint was progression-free survival (PFS). Baseline M-protein was detected in 117 of 235 patients (49.8%), most commonly immunoglobulin M (IgM) (65.8%). M-protein positivity was associated with a higher frequency of plasmacytic differentiation (39.6% vs. 16.2%; adjusted OR 3.78). M-protein-positive patients had shorter PFS than M-protein-negative patients (median, 50.9 months vs. not reached; log-rank p = 0.044), and this association remained in multivariable analysis (hazard ratio [HR] 1.58). Overall survival (OS), progression of disease within 24 months (POD24), and histologic transformation did not differ significantly by M-protein status. Among 70 patients with evaluable post-treatment data, M-protein response of at least partial response (PR) was highly specific for clinical response and had a high positive predictive value, but response depth did not predict PFS. In uniformly tested MZL patients requiring systemic therapy, baseline M-protein identifies a subgroup enriched for plasmacytic differentiation and associated with shorter PFS. Post-treatment M-protein decline can support response confirmation when present, but it should not be used as a surrogate endpoint for durable disease control without prospective validation.
ABSTRACT Long‐term real‐world data on Luspatercept (Luspa) in lower‐risk myelodysplastic syndromes with ring sideroblasts (MDS‐RS) and transfusion‐dependent anemia (RBC‐TD) who are refractory or ineligible to erythropoiesis‐stimulating agents (ESAs) remain limited. Despite evidence of efficacy from clinical trials and real‐world studies, long‐term data in routine clinical practice are scarce, particularly regarding its effects on non‐erythroid lineages. Furthermore, there is currently no consensus on the total duration of treatment, especially in non‐responding cases. Thus, we analyzed 48 patients with low‐risk MDS‐RS treated with Luspa for ESA‐refractory RBC‐TD. Response was assessed at 6 months, 1 year, and 2 years according to International Working Group (IWG) 2018 criteria. At 6 months, 23/42 (54.8%) and 15/42 (35.7%) patients reached a response and transfusion independence, respectively. At 1 year, 16/30 (53.3%) patients showed a response, including 12 who already responded at 6 months. At 2 years, 10/20 (50%) patients maintained response and 2/20 (10%) were de novo responders. Treatment was well tolerated, with no significant adverse events reported; 21 (43.8%) patients discontinued Luspa, principally due to lack of response. After a median follow‐up of 29.8 months (95% CI: 24.4–35.2), 6‐month responders had longer overall survival in a landmark analysis. Exploratory analyses identified associations of 6‐month response with additional somatic mutations and the SF3B1 hotspot mutation, the latter retained in the multivariable model; monocyte count was associated with 2‐year response. Neutrophil counts significantly increased at 1 year compared with baseline, while platelet counts remained stable. Intriguingly, monocytes were increased at the three time points compared to baseline. Specifically, long‐term responders presented higher levels of neutrophils and monocytes, as well decreased level of LDH, compared with non‐responders. Responses were observed during long‐term treatment, mainly in patients who had responded at earlier assessments. Decreasing evaluable sample sizes and the retrospective design limit interpretation. Associations with survival and non‐erythroid blood counts require confirmation and should not be interpreted as causal effects.
ABSTRACT MLN‐Eo (Myeloid/Lymphoid Neoplasms with Eosinophilia) harboring FLT3 rearrangement is an extremely rare hematologic malignancy for which standardized treatment guidelines are currently lacking. This systematic review synthesizes the largest cohort (39 cases) to date of FLT3‐ rearranged MLN‐Eo. The available evidence supports the role of hematopoietic stem cell transplantation (HSCT) as the cornerstone for achieving long‐term survival and as a potentially curative intervention under current treatment modalities. Tyrosine kinase inhibitors (TKIs) can be used as bridging therapy to transplantation by inducing remission and reducing tumor burden. For patients ineligible for HSCT, TKI‐based regimens (combined with chemotherapy) are recommended for disease control, while chemotherapy alone is strongly discouraged due to uniformly poor outcomes. These findings provide a practical treatment framework based on the currently available evidence and may help inform clinical decision‐making for this rare and challenging disease.
ABSTRACT Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in Western countries. The introduction of targeted therapies has expanded first‐line treatment options, which differ across multiple relevant dimensions, making therapeutic decisions increasingly challenging. A multi‐criteria decision analysis (MCDA) was conducted to identify and quantify the importance of key treatment selection criteria and to evaluate available first‐line alternatives for patients with mutated and unmutated immunoglobulin heavy‐chain variable region (IGHV mut /IGHV unmut ) gene status, from the perspective of clinicians, patients, payers, and methodologists. The analysis focused on targeted therapies recommended by European Society for Medical Oncology (ESMO) guidelines and reimbursed in Italy, including ibrutinib, acalabrutinib, zanubrutinib, venetoclax + ibrutinib, and venetoclax+obinutuzumab. The MCDA was developed in accordance with International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Good Practice recommendations, using the MACBETH (Measuring Attractiveness by a Categorical‐Based Evaluation Technique) method to elicit stakeholder preferences. Decision criteria were selected based on literature review, stakeholder input, and data availability. Preferences were collected from 20 stakeholders (nine clinicians, five patients, six payers/methodologists) via structured questionnaires. Six criteria were selected: efficacy, safety, quality of life (QoL), drug cost, convenience of administration, and treatment duration. Efficacy and safety emerged among the most important criteria across all groups, with efficacy particularly prioritized in the IGHV unmut population. Among the other criteria, notable differences emerged between stakeholder groups: clinicians assigned relatively greater importance to treatment duration, especially in the IGHV mut population; patients prioritized QoL more than other groups; payers and methodologists gave more weight to drug cost than clinicians and patients. In the IGHV mut population, venetoclax + ibrutinib, and zanubrutinib were the most valued options. In the IGHV unmut population, second‐generation Bruton tyrosine kinase inhibitors (zanubrutinib and acalabrutinib) ranked highest. Sensitivity analyses confirmed the robustness of these findings. This is the first MCDA study applied to CLL treatment in Italy. It highlights the value of structured, stakeholder‐informed approaches in supporting value‐based treatment decisions.
ABSTRACT CPX‐351, a liposomal formulation of cytarabine and daunorubicin, has been approved patients with secondary/high‐risk acute myeloid leukemia including therapy‐related acute myeloid leukemia or AML with myelodysplasia‐related changes according to the WHO 2016 classification. The aim of this study was to determine the efficacy and safety of CPX‐351 in 283 patients with AML registered in the PETHEMA database. Evolving outcome results were analyzed comparing early treated patients (before‐2022, N = 147) with those treated after Spanish financial approval (since‐2022, N = 136). The CR/CRi rate was 54% in the overall cohort, without significant differences comparing both time periods. By contrast, early death rates at day + 30 and day + 60 were higher in early period patients (11.6 vs. 5.1% and 17 vs. 8.1%, p = 0.03 and p = 0.031). Consequently, more patients could undergo HSCT in the latter treatment period (33.8% vs. 25.2%, p = 0.04). Patients treated with CPX‐351 since 2022 showed a significantly higher unadjusted 2‐year OS probability compared with patients treated earlier [40.3% (95% CI: 26.3–62.4) versus 25.2% (95% CI: 18.6–34.1), P = 0.017]. However, treatment period was not independently associated with OS in multivariable analysis. Only TP53 wild‐type status [HR 0.51 (95% CI: 0.25–1.05)] and achievement of MRD negativity after induction [HR 0.54 (95% CI: 0.29–1.0)] remained independently associated with improved OS. Overall, outcomes after CPX‐351 appeared to improve over time in unadjusted analyses; however, the absence of an independent effect of treatment period and differences in patient selection between periods preclude attributing this improvement specifically to a temporal learning effect.
