Impact of BCL3 Expression and Clinical-Hematologic Risk Factors on Early Molecular Response, Reticulin Fibrosis, and Survival Outcomes in Chronic Myeloid Leukemia: A Prognostic Cohort Study.

Background: BCL3, an atypical I-kappa-B family member and NF-κB transcriptional co-regulator, has been implicated in haematological malignancies, yet its prognostic significance in chronic myeloid leukaemia (CML) remains unclear. Objectives: To evaluate the association between baseline bone marrow BCL3 expression and treatment failure in CML patients receiving tyrosine kinase inhibitors (TKIs). Methods: In a retrospective cohort of 100 consecutive newly diagnosed chronic-phase CML patients with prospectively recorded clinical and laboratory data, BCL3 mRNA expression was measured by quantitative RT-PCR (SYBR Green) on unfractionated bone marrow aspirate samples, using the delta-delta Ct method with beta-actin as the housekeeping gene. Treatment failure was defined as progression to accelerated/blast phase or death during follow-up, and failure-free survival (FFS) as the time to the first of these events. Analyses included ROC analysis with an exploratory Youden-derived cut-off, multivariable logistic regression adjusted for the clinical variables of the EUTOS long-term survival (ELTS) score plus spleen length, or for age and leukocyte count, with bootstrap internal validation, and Cox proportional-hazards regression. Results: Thirty-five patients (35%) experienced treatment failure (16 progression, 19 death without documented progression); 72 of 82 evaluable patients achieved major molecular response (MMR) at 12 months. BCL3 was significantly higher in the treatment failure group (median 1.80 (1.35-2.04) vs 0.80 (0.60-1.20); P < 0.001). BCL3 discriminated treatment failure with an AUC of 0.827 (95% CI 0.736-0.918); the exploratory cut-off of 1.60 gave a sensitivity of 68.6% and specificity of 89.2% (optimism-corrected 65.2% and 87.8%). BCL3 remained associated with treatment failure after adjustment for the ELTS clinical variables and spleen length (OR per unit 11.48 (95% CI 4.05-32.56)) and for age and leukocyte count (OR 8.57 (95% CI 3.21-22.88); optimism-corrected model AUC 0.846). High BCL3 was associated with shorter FFS (HR 7.77 (95% CI 3.75-16.08); 24-month FFS 22.6% vs 84.1%) and with lower MMR attainment at 12 months (9/18 vs 63/64 evaluable patients). Conclusions: Higher baseline BCL3 expression is a prognostic factor associated with treatment failure in TKI-treated chronic-phase CML in this cohort. The 1.60 threshold is exploratory and internally derived; external validation is required before BCL3 can be used for risk stratification or treatment decisions.