BTK Inhibitor Ibrutinib/Zanubrutinib Plus Bendamustine and Rituximab As the Initial Treatment for Chronic Lymphocytic Leukemia/ Small Lymphocytic Leukemia：a Single Arm Real-World Study
Authors: Zhu Huayuan , Wu Wei , Sha Yeqin , Jin Ze , Yang Yilian , Qiu Jingyan , Ding Chongyang , Wang Zhen , Shi Chuanbing , Peng Chen , Mi Hongling , Chen Ruize , Wang Li , Fan Lei , Xu Wei , Li Jianyong 
Published: November 2021

Abstract
Introduction
To evaluate the safety and efficacy of BTK inhibitor ibrutinib or zanubrutinib plus bendamustine and rituximab (iBR or zBR) as the initial treatment for chronic lymphocytic leukemia (CLL)/ small lymphocytic leukemia (SLL) patients, we conducted this single-arm retrospective observational study.
Methods
We enrolled patients over 18 years old with CLL/SLL who required treatment. iBR or zBR were administrated as following, ibrutinib 420 mg daily or zanubrutinib 160 mg twice daily from day 0, rituximab 375 mg/m 2 on day 0 of cycle 1 and 500 mg/m 2 on day 0 of cycle 2-6, bendamustine (70 mg/m 2, days 1-2), 28 days per cycle, ibrutinib or zanubrutinib was maintained at least 2 years and planned to discontinue in patients with undetectable minimal residual disease (uMRD) in both peripheral blood (PB) and bone marrow (BM). Response assessment was conducted after 3 cycles and 2 months after 6 cycles (EOT) according to 2018 iwCLL criteria in patients with CLL and 2014 Lugano criteria in patients with SLL. Minimal residual disease (MRD) in PB was detected after each cycle and MRD in BM was detected after 3 and 6 cycles by flow cytometry. uMRD was defined as less than 1 CLL cell per 10 4 leukocytes by flow cytometry.
R esults
At data cut-off (15 th June 2021), 10 treatment-naïve patients in the First Affiliated Hospital of Nanjing Medical University were enrolled, with 9 CLL and 1 SLL. All patients had completed planned six cycles of iBR(n=8) or zBR(n=2). The median age was 56 years old. Unmutated IGHV was detected in 30.0% (3/10) patients, one patient (1/8, 12.5%) had both del(17p) and TP53 mutation. Among 9 patients with CLL, 3 (33.3%) was classified as low-risk group according to CLL-IPI, 4(44.4%) in intermediate-risk, 1(11.1%) in high-risk group and 1(11.1%) in very-high risk group (Table 1). After 3 cycles, the overall response rate (ORR) was 100%, and complete remission (CR) rate was 20.0%, one patient achieved CRi (CR with incomplete bone marrow recovery). 50% (5/10) and 37.5% (3/8) patients achieved uMRD in PB and BM respectively. The ORR was 100% (10/10) and CR rate was 60.0%, 3 patients achieved CRi (30.0%) at EOT. 60.0% (6/10) and 50.0% (5/10) patients achieved uMRD in PB and BM respectively (Table 2, Figure 1). The most common hematological toxicity events were neutropenia and thrombocytopenia, and the non-hematological toxicity events were malaise, pruritus, nausea, vomiting and hematuria. The occurrence rate of grade 3 to 4 neutropenia and agranulocytic fever were 40.0% (4/10) and 10.0% (1/10) respectively. The most common ibrutinib-related AE were purpura, rash, diarrhea and hematuria. The occurrence rate of AE induced discontinued ibrutinib or zanubrutinib were 30.0% (3/10).
Conclusion
Here, we first reported the efficacy and tolerance of BTK inhibitor plus BR as initial treatment in a small cohort of CLL/SLL patients. BTK inhibitor plus BR could achieved high response rate and high proportion of undetectable MRD，with manageable toxicity.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.