Page 67 - 2021_09-Haematologica-web

Zanubrutinib in treatment naïve del(17p) CLL/SLL
Introduction
Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have historically been treated with combination chemotherapy and immunotherapy with success; however, many patients do not have sustained responses in part due to genomic aber- rations that impair responsiveness to therapy. One aberra- tion found in patients with CLL/SLL is the deletion of chromosome 17p13.1 [del(17p)]; these patients have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy, with reduced rates of overall sur- vival (OS) and worse clinical outcomes.1,2 del(17p) results in the mono or biallelic loss of the TP53 gene, which encodes the tumor suppressor p53, a multifunctional tran- scription factor important for cellular response to DNA damage, including cell cycle arrest and apoptosis.3 Most patients with del(17p) also have a mutation of the other TP53 allele and therefore lack wild-type TP53, leading to genomic instability and reduced responsiveness to cyto- toxic chemotherapy.2 The incidence of del(17p) is approx- imately 5-8% of patients with CLL at diagnosis and increases with each relapse.4,5
Novel targeted therapies are therefore the preferred treatment modality for previously untreated patients whose disease bears the del(17p) mutation.6,7 Several new agents are approved by the US Food and Drug Administration and European Medicines Agency (EMA) for adult patients with CLL/SLL regardless of del(17p) sta- tus, including the BTK inhibitors ibrutinib and acalabruti- nib. In the RESONATE study of ibrutinib versus ofatu- mumab in patients with relapsed or refractory (R/R) CLL/SLL,8 89% of ibrutinib-treated patients with del(17p) achieved an objective response with long term follow-up.9 Similar results were observed in the single-arm RES- ONATE-17 study in R/R CLL10 in which 83% of patients achieved an objective response; the 24-month progres- sion-free survival (PFS) was 63%. Acalabrutinib, a second- generation BTK inhibitor, has been approved recently for treatment-naïve (TN) patients with CLL/SLL regardless of del(17p) status based on results from the ELEVATE TN study.11,12 Notably, of the patients with del(17p) in that study, only 16 were assigned to the single-agent acalabru- tinib arm.
Other small molecule inhibitors approved in patients with CLL/SLL and del(17p) include the BCL-2 inhibitor venetoclax13 and the phosphatidylinositide-3-kinase (PI3K)-δ inhibitor idelalisib.14 Stilgenbauer and colleagues reported the results of venetoclax treatment in 158 mostly R/R del(17p) patients,15 including a 77% overall response rate (ORR) and an estimated 24-month PFS of 50%. Notably, only five patients in this study were TN. In the CLL14 trial which compared venetoclax and obinutuzum- ab to chlorambucil and obinutuzumab in TN CLL, 17 patients assigned to the venetoclax arm had del(17p).16 Similarly, studies supporting the approval of idelalisib together with rituximab in the frontline setting by the EMA included few TN CLL/SLL patients with del(17p).17,18 Collectively, only limited data are available for novel tar- geted therapies for previously untreated patients with del(17p) CLL/SLL, and no large multi-center studies have systematically examined this specific population.
Zanubrutinib (BGB-3111) is a next-generation BTK inhibitor with favorable oral bioavailability and high specificity for BTK, exhibiting comparatively lower off- target activity than ibrutinib for structurally related kinas-
es such as epidermal growth factor receptor (EGFR), inter- leukin-2 inducible kinase (ITK), and Src family kinases.19 The safety, pharmacokinetics, pharmacodynamics, and preliminary activity of zanubrutinib were investigated in a phase I/II study of patients with multiple B-cell malignan- cies in which high level, sustained BTK occupancy was noted in both peripheral blood and lymph nodes at the recommended phase II dose of 160 mg twice daily (bid).20 Encouraging activity was observed in a cohort of 78 patients with both TN and R/R CLL/SLL, including in a subset of 16 patients with del(17p) or TP53 mutation who achieved a 100% ORR.20 Activity of zanubrutinib was also observed in a separate phase II trial of 91 R/R CLL/SLL patients in China, including in a subset of 17 patients with del(17p) who achieved a 88.2% ORR.21 Zanubrutinib has recently received accelerated approval in the United States for adult patients with mantle cell lymphoma who have received at least one prior therapy22 and is currently under- going further clinical testing in several prospective, multi- center, randomized phase III trials in CLL/SLL.
The SEQUOIA trial (clinicaltrialsgov. Identifier: NCT03336333) is an open-label, multi center, randomized phase III study of TN patients with CLL/SLL. Patients without centrally confirmed del(17p) were randomized to receive either zanubrutinib 160 mg bid until unacceptable toxicity or disease progression (PD), or six cycles of ritux- imab and bendamustine. Considering the poor outcomes associated with any standard chemoimmunotherapy regi- men in patients with del(17p), those with centrally con- firmed del(17p) during screening for SEQUOIA were not randomized but assigned to single-agent zanubrutinib in a separate cohort (Arm C). This is the first report of the safe- ty and efficacy results in this high-risk del(17p) patient cohort.
Methods
Study design and population
Eligible patients had confirmed CLL/SLL requiring treatment per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) definition.23 TN adults were eligible if either aged ≥65 years or unsuitable for treatment with fludarabine, cyclophos- phamide, and rituximab (FCR) and an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.24 Centrally con- firmed del(17p) by fluorescence in situ hybridization with >7% aberrant nuclei present was required. Patients had adequate end- organ function, including absolute neutrophil count (ANC) ≥1,000/mm3 and platelet count ≥75,000/mm3. For patients with bone marrow involvement, ANC ≥750/mm3 and platelet count ≥50,000/mm3 were allowed. Patients with history of atrial fibrilla- tion and/or long-term anticoagulation, or those requiring moder- ate or strong CYP3A inhibitors, could enroll.25 All Arm C patients were assigned to receive zanubrutinib (160 mg bid) until intoler- ance or PD.
This study was conducted according to principles of the Declaration of Helsinki and the International Conference on Harmonization guidelines for Good Clinical Practice and approved by the Institutional Review Board/Ethics Committee at each participating site. All patients provided written informed consent. This study adhered to CONSORT-10 guidelines for reporting.26
Objectives and assessments
Key objectives for Arm C included assessments of ORR, PFS,
haematologica | 2021; 106(9)
2355