A Single Center Real World Study of Outcome and Resistance of Bruton Tyrosine Kinase Inhibitors (BTKi) in Chinese Patients with Chronic Lymphocytic Leukeima/Small Lymphocytic Lymphoma
Authors: Zhu Huayuan , Dai Luomengjia , Sha Yeqin , Lu Xiao , Qian Siqi , Qiu Tonglu , Miao Yi , Xia Yi , Qin Shuchao , Zhou Ziyuan , Wu Wei , Fan Lei , Xu Wei , Li Jianyong 
Published: December 2023

Introduction
Acquired BTK/PLCG2 mutations remain to be the driver of Bruton Tyrosine Kinase inhibitor (BTKi) resistance. But the underlying mechanisms need to be further explored. In this study, we retrospectively analyzed clinical and biological characteristics of BTKi-treated CLL patients and report the outcome and resistance in our center (the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital).
Method
262 patients treated with single BTKis continuously were collected and follow up the outcome in our center. Progression-free survival (PFS) was defined as from BTKi initiation to disease progression on BTKi. Next-generation sequencing (NGS) and High sensitivity droplet digital PCR (ddPCR) acquired at treatment initiation /or at the time of disease progression were used to describe mutational landscape. Kaplan-Meier method and the log-rank test were used for analysis.
Results
A total of 262 patients were enrolled from January 2014 to March 2023, and the median age was 63 (range 28-88) years. Ibrutinib, Zanubrutinib, Orelabrutinib were administered in 55.3%,18.3% and 17.9% of patients respectively, in addition to 6 patients with Acalabrutinib and one with Loxo-305, among them 47.7% (125/262) received BTKi as first line treatment. With a median follow up of 27.3 months, 208 patients were in durable remission while 54 patients relapsed, the median exposure of BTKi was 26.8 (range, 1-73.8) sand 27.7 (range, 3-69.8) months respectively. The median PFS was 5.8 years (5.0-NA, 95% CI) for the whole cohort.
Clinical and biological characteristics of both cohorts at initiation of BTKi treatment were described and compared in Table 1. Higher proportion of bulky disease (50.0% vs 23.5%), IGHV unmutated status (84.3% vs 50.5%), del(17p) (44.7% vs 12.9%), TP53 mutation (37.8% vs 15.2%), TP53 aberrations (62.5% vs 24.3%) and complex karyotype (40.5% vs 21.1%) were shown in the BTKi relapsed cohort as compared to responsive cohort. Inferior PFS was observed in patients with TP53 aberration vs without TP53 aberration ( 45.6 mos vs not reached, p&lt;0.0001), unmutated IGHV vs mutated IGHV (56.2 mos vs not reached, p=0.0005), with del(17p) vs without del(17p) (36.1 mos vs not reached, p&lt;0.0001), with complex karyotype and without complex karyotype (69.8 mos vs not reached, p=0.0401), bulky disease vs no bulky disease (45.6 mos vs 69.8 mos, p=0.0006) and elevated LDH vs normal LDH (66.5 mos vs not reached, p=0.0083). Moreover, patients with del(11q) or BTKi given as second or greater line showed a tendency of inferior PFS ( p= 0.1963, p= 0.0735, respectively).
Regarding the relapsed cohort, 43 patients displayed CLL progression while 11 patients displayed Richter transformation (RT, including 1 Hodgkin lymphoma [HL]) , the median time from initiation to progression were 33.7 months and 9.5 months, respectively（p&lt;0.0001). BTK/PLCG2 mutations were the most common mutation at the timepoint of disease progression. By integrating NGS and ddPCR results, 54.9% (28/51) relapsed patients acquired BTK/PLCG2 mutation. BTKC481S mutation was the dominant hotspot mutation in all kinds of BTKi relapsed cases. Other mutations at the C481 site included C481R, C481Y, C481F. However, BTKT474 mutation was only detected in Orelabrutinib-resistant cases (Figure 1). 6 patients presented with multi-hit mutations.
Treatment after disease progression on BTKis is still challenging. In our relapsed cohort, the median PFS was 5.7 months and poorer in RT as compared with CLL progression (3.0 months vs 6.7 months, p= 0.0874). Venetoclax-based regimen might be an effective salvage therapy which could showed a benefit trend in PFS as compared to other post BTKi therapy (10.1 months vs 3.1 months, p= 0.1818).
Conclusion
In our real world study, patients with IGHV unmutated status, TP53 aberrations, bulky disease and elevated LDH showed inferior PFS. Acquired BTK/PLCG2 mutations remained to be key drivers of BTKis resistance and BTKC481S mutation was the dominant mutation, while BTKT474 mutation was only detected in Orelabrutinib-resistant patients. The prognosis was rather poor for relapsed patients especially for RTs, treatment strategy after disease progression remains to be optimized.