Retrospective Analysis of Spanish Real-World Data Investigating First Line Treatment Patterns in a Representative Sample of Chronic Lymphocytic Leukemia Patients
Authors: Dostalova Zuzana , Strobel Kai , Baumann Tycho , Miras Fatima , Martínez-Lopez Joaquín , Garcia Vela José Antonio , Schilling Stefan , Rückert Markus 
Published: December 2024

Introduction: The introduction of BTK inhibitors (BTKi) and the BCL2 inhibitor (BCL2i) venetoclax has significantly transformed the treatment landscape of chronic lymphocytic leukemia (CLL) in Spain in real-world clinical practice. Previously, decisions between different options of chemoimmunotherapy (CIT) were primarily based on patient age, comorbidities, and physical condition. Currently, treatment choices are largely guided by the patient's genetic risk profile. However, there is a scarcity of real-world observational data on how these updated guidelines are being implemented.
Methods: A retrospective, observational study collecting data in a structured eCRF from patients requiring first line treatment for CLL was initiated in 29 national institutions (14% non-university and 86% university hospitals, representing 16% of patients from non-university and 84% of patients from university hospitals) in 2022. The age, sex, stage, genetic risk factors, comorbidities and reason for treatment decision were recorded.
Results: Data from 141 pts (median age 72 yrs, 60% male) managed at 25 university hospitals (UH) and 4 non-university hospitals (NUH) who started 1L treatment between 07/01/2021 and 06/30/2022 were included in the analysis. At treatment initiation, 60% were staged Binet A or B and 40% Binet C. Patients receiving BTKi-based and CIT treatment were more frequently staged with an advanced disease stage Binet C, while those treated with BCL2i were less frequently stage C (BTKi: 39/98, 40%; BCL2i: 5/24, 21%; CIT: 11/18, 61%). Largely consistent with Binet C staging, the reasons to initiate treatment were anemia or thrombocytopenia in 55% (77/141; BTKi: 55/98, 56%; BCL2i: 8/24, 33%; CIT: 13/18, 72%; [chi^2 = 6.7; p = 0.035]) and constitutional symptoms in 59% of patients (83/141; BTKi: 55/98, 56%; BCL2i: 14/24, 58%; CIT: 14/18, 78%). Of the 141 study pts, 96% (135/141; BTKi: 93/98, 95%; BCL2i: 24/24, 100%; CIT: 17/18, 94%) were tested for genetic risk factors (e.g. FISH del11q/17p, IGHV mutational status, karyotype), thereof 80% (108/135; BTKi: 80/93, 86%; BCL2i: 19/24, 79%; CIT: 9/17, 50%; [chi^2 = 12.16; p = 0.0023]) had one or more genetic risk factors. TP53 alterations were more frequently reported for patients treated with a targeted agent (BTKi: 22/93, 24%; BCL2i: 5/24, 24%; CIT: 1/17, 6%). The combination of TP53 aberrant and IGHV unmutated did not differ statistically between treatment groups due to low patient numbers, however, no patient with both risk factors was reported for CIT-treated patients (BTKi: 9/93, 10%; BCL2i: 3/24, 13%; CIT: 0/17, 0%). Of 141 pts, 93 (66%) had recorded at least one comorbidity. Comorbidity was more often reported for BTKi treated pts compared to CIT treatment (BTKi: 67/98, 68%; BCL2i: 15/24, 63%; CIT: 10/18, 56%). However, heart insufficiency was significantly noted in the CIT group (BTKi: 6/67, 9%; BCL2: 1/15, 7%; CIT: 5/10, 50%) and reported cardiac arrhythmia did not appear to play a role in treatment decision (BTKi: 9/67, 13%; BCL2i: 0/15, 0%; CIT: 2/10, 20%).
Conclusions: Essential genetic factor testing, such as FISH and IGHV mutation status for prognostic risk stratification, were performed in most pts in this real-world cohort from Spain. Consequently, a biology-informed choice of treatment led to preference of targeted agents in most of the high-risk population known to have poorer outcome with CIT. Strikingly, BCL2i pts were less frequently stage C. Advanced disease stage Binet C was associated with BTKi based or CIT treatment. In patients with comorbidities, BTKis were preferred while there was no clear pattern regarding cardiovascular comorbidity. In summary, our observational study suggests that multiple factors influence the selection of treatment in the real-world setting and treatment decisions based on recommendations regarding the genetic risk-stratification are being implemented.