Clinical Characteristics, Treatment Strategies, and Outcomes for CLL Patients with BTK Mutation; A Single Center Study
Authors: Ammad Ud Din Mohammad , Knepper Todd C , Chavez Julio C. , Nodzon Lisa , Saeed Hayder , Gaballa Sameh , Sokol Lubomir , Dong Ning , Isenalumhe Leidy Lismeris , Bello Celeste M. , Shah Bijal D. , Pinilla-Ibarz Javier 
Published: December 2023

Background:
The population of patients with chronic lymphocytic leukemia (CLL) with disease refractory to Bruton tyrosine kinase inhibitors (BTKi) is growing given the widespread use of these agents. We conducted a single center study to evaluate the disease characteristics, treatment strategies, and outcomes for patients with BTK mutation.
Methods:
The archives of personalized genetic medicine at the H Lee Moffitt Cancer Center and Research Institute were accessed to identify cases of BTK mutation confirmed by next generation sequencing that were reviewed between 2016-2023. Individual records of patients identified were examined to gather data regarding clinical history, genetic testing, and treatment following detection of BTK mutation according to an Institutional Review Board approved protocol. Each patient record was followed for 2 years post detection of BTK mutation or till July 2023, whichever came first, to determine progression free survival (PFS) on next line of therapy.
Results:
A total of 30 patients were identified. The median age was 67.5 (interquartile range (IQR) 61-73.5) years and 15 (50.0%) of the patients were female. Twenty-three (76.7%) of the patients were on ibrutinib, while 7 (23.3%) were on acalabrutinib. Only 4 (13.3%) patients received BTKi as the first line of therapy. The majority of patients received BTKi as the second line of treatment (46.7%), while 30.3% received it as 3rd line, and 10.0% received it as 4th line. The median time to progression on BTKi 52.5 months.
The most common presentation of progression was worsening lymphocytosis alone (36.7%), followed by lymphadenopathy (LAD) and lymphocytosis (33.3%), and LAD alone (20.0%). The most common BTK mutation variant seen was C481S that occurred in 21 (70.0%) cases. C481S mutation occurred independently in the absence of another BTK variant mutation in 18 of these patients. C481R mutation was seen in 20.0% of the cases and was always seen concurrently with another variant mutation (either C481F, C481Y, or C841S). The median number of other mutations present concurrently with BTK mutation was 5 (IQR 3-6). Half (50.0%) of the cases had concurrent TP53 mutation while 30.0% had concurrent PLCG2 mutation. Other commonly seen mutations included NOTCH1 (26.7%), SF3B1 (26.7%), ATM (23.3%), MED12 (16.7%), ASXL1 (16.7%), BIRC3 (13.3%), and TET2 (13.3%) (Figure 1).
Following confirmation of BTKi mutation, most patients (63.3%) were started on a venetoclax based regimen. Six patients (20.0%) continued on the same BTKi with addition of venetoclax, 10 (33.3%) patients were switched to venetoclax and immunotherapy (either obinutuzumab or rituximab), and 3 (10.0%) patients were started on single agent venetoclax. Two patients (6.7%) were switched to a non-covalent BTKi while another 2 (6.7%) patients were kept on the same BTKi with the addition of immunotherapy. Three (10.0%) patients were taken to chimeric T cell receptor (CAR-T) cell therapy of which one patient had no response and was started on salvage treatment with duvelisib. Another two patients (6.7%) had Richter's transformation and were treated with chemoimmunotherapy. The overall median PFS for next line of therapy was 18 months with no statistical difference between venetoclax and non-venetoclax regimens (not reached vs 8 months, p=0.25).
Conclusion:
Our results reveal that durable responses can be achieved by switching to venetoclax based regimens in patients with BTKi. Though the early results of the use of noncovalent BTKi in this setting aree encouraging, the durability of response is limited as new BTK mutations are selected and future therapeutic alternatives are needed for these subset of patients.