[Clinical and molecular biological characterization of patients with accelerated chronic lymphocytic leukemia].

Objective: To investigate the clinical and molecular biological characteristics of patients with accelerated chronic lymphocytic leukemia (aCLL) . Methods: From January 2020 to October 2022, the data of 13 patients diagnosed with aCLL at The First Affiliated Hospital of Nanjing Medical University were retrospectively analyzed to explore the clinical and molecular biological characteristics of aCLL. Results: The median age of the patients was 54 (35-72) years. Prior to aCLL, five patients received no treatment for CLL/small lymphocytic lymphoma (SLL), while the other patients received treatment, predominantly with BTK inhibitors. The patients were diagnosed with aCLL through pathological confirmation upon disease progression. Six patients exhibited bulky disease (lesions with a maximum diameter ≥5 cm). Positron emission tomography (PET) -computed tomography (CT) images revealed metabolic heterogeneity, both between and within lesions, and the median maximum standardized uptake value (SUVmax) of the lesion with the most elevated metabolic activity was 6.96 (2.51-11.90). Patients with unmutated IGHV CLL accounted for 76.9% (10/13), and the most frequent genetic and molecular aberrations included +12 [3/7 (42.9% ) ], ATM mutation [6/12 (50% ) ], and NOTCH1 mutation [6/12 (50% ) ]. Twelve patients received subsequent treatment. The overall response rate was 91.7%, and the complete response rate was 58.3%. Five patients experienced disease progression, among which two patients developed Richter transformation. Patients with aCLL with KRAS mutation had worse progression-free survival (7.0 month vs 26.3 months, P=0.015) . Conclusion: Patients with aCLL exhibited a clinically aggressive course, often accompanied by unfavorable prognostic factors, including unmutated IGHV, +12, ATM mutation, and NOTCH1 mutation. Patients with CLL/SLL with clinical suspicion of disease progression, especially those with bulky disease and PET-CT SUVmax ≥5, should undergo biopsy at the site of highest metabolic uptake to establish a definitive pathological diagnosis.

[Clonality relatedness and molecular characteristics of Richter transformation].

Objective: To investigate the clinical, genetic, and clonality related aspects of individuals with Richter transformation (RT) . Methods: From January 2019 to December 2021, 18 RT patients with diagnoses at the First Affiliated Hospital of Nanjing Medical University (Pukou CLL center) were retrospectively examined. The immunoglobin heavy variable (IGHV) gene usage and IGHV-D-J rearrangement pattern of diagnosed CLL/SLL and transformed diffuse large B-cell lymphoma (DLBCL) were compared to determine the clonality relatedness. To investigate the risk factors of RT, Clinical and laboratory data from patients with newly diagnosed CLL/SLL and transformed DLBCL were gathered. Results: The median age of RT was 56.5 (41-75) years old. 17 patients transformed to DLBCL and 1 transformed to Hodgkin lymphoma (HL) . Of 17 individuals who had DLBCL transformation, 15 had CLL/SLL-related clonality and 2 had unrelated clonality. Next-generation sequencing (NGS) analysis of 11 paired initially diagnosed treatment-naive CLL/SLL and RT DLBCL found that EGR2、TP53 and NOTCH1 were among the most frequently mutated genes both in treatment-naive CLL/SLL and in RT DLBCL. In several cases, specific mutations were gained or lost throughout RT, indicating clonal evolution. Among 10 patients before exposure to BTK inhibitors before RT, four patients acquired BTK mutation. The aforementioned mutations should be considered high-risk variables for transformation; in addition, TP53 and EGR2 mutations could be linked to a poor prognosis following RT in patients receiving a cocktail of new medicines. Conclusion: Most RT DLBCL patients in our center are clonality related (15/17, 88.2% ) and we recommend all qualified centers to evaluate clonality relatedness of RT DLBCL patients. There was some variability in the mutational landscape between DLBCL that had undergone a transformation and initially diagnosed, treatment-naive CLL/SLL. The underlying molecular mechanism of RT needs more research.

[Comparison of four prognostic scoring system in patients with early asymptomatic chronic lymphocytic leukemia patients].

Objective: To compare the prognostic value of four prognostic models in predicting time to first treatment (TTFT) in patients with Binet A Chinese chronic lymphocytic leukemia (CLL) . Methods: This retrospective analysis included one hundred and ten patients with Binet A CLL, initially diagnosed in the First Affiliated Hospital of Nanjing Medical University (Pukou CLL center) from June 2009 to January 2020. Risk stratification was conducted according to IPS-E, CLL-IPI, CLL1-PM, and Barcelona-Brno prognostic models. Results: Among 110 patients with Binet A CLL patients, the median age was 58 (25-84) years. The median follow-up time was 35 (4-189) months, and 57 (51.8%) patients met the indication for treatment due to symptomatic disease progression during follow-up. Log-rank analysis of nine variables was conducted involving age, Rai stage, absolute lymphocyte count (ALC) , lymph node size, lymphocyte doubling time (LDT) , ß(2)-Microglobulin, IGHV status, TP53, and Del (11q) . Additionally, Rai Ⅰ-Ⅲ, ALC>15×10(9)/L, palpable lymph node size ≥1cm, ß(2)-Microglobulin>3.5 mg/L, unmutated IGHV, TP53 mutation or deletion, and 11q deletion were independent risk factors of TTFT. Predictive value of each model was assessed by Harrel C-index and Akaike information criterion (AIC) with CLL1-PM (C-index=0.736, AIC=777) , followed by CLL-IPI (C-index=0.722, AIC=933) , IPS-E (C-index=0.683, AIC=1004) , and Barcelona-Brno prognostic model (C-index=0.663, AIC=986) . Conclusion: All four prognostic models effectively predicted TTFT. IPS-E might be an ideal model to guide clinical surveillance because of its easy accessibility and low expenses in routine clinical practice. Therefore, for patients receiving fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) examination at diagnosis, CLL-IPI or CLL1-PM could be applied to evaluate their prognosis more comprehensively.