Page 73 - 2021_09-Haematologica-web

Zanubrutinib in treatment naïve del(17p) CLL/SLL
study appears at least comparable with the reported ibru- tinib experience. Median time to response essentially was defined by the first scheduled response assessment (Figure 1C), consistent with reduction in target lesion size (Online Supplementary Figure S1A) and resolution of cytopenias (Online Supplementary Table S3). Consistent with previous studies of other BTK inhibitors,12,32,37 CR were uncommon with short follow-up; longer follow-up will be needed to more precisely define the CR rate. Response rates appear to be similarly high regardless of coincident risk factors, including IGHV mutational status and complex karyotype status, though the low number of non-responders may limit the ability to detect meaningful differences between subgroups.
In the UK LRF CLL4 trial, del(17p) in >20% of nuclei was found to be independently associated with shorter PFS in patients treated with chemoimmunotherapy.39,40 As expected, patients with a higher burden of del(17p) were associated with a higher rate of poor prognostic factors such as unmutated IGHV status and complex karyotype. When examining ORR and progression events in the cur- rent study, ORR appeared to be similar in patients without and with del(17p) in ≥20% of nuclei (Online Supplementary Table S4), suggesting that zanubrutinib has preserved activity in high-risk patients with enrichment of malig- nant cells for del(17p). This is comparable to the activity seen in the RESONATE-17 trial of R/R patients with del(17p) treated with ibrutinib.10
Ten patients progressed on study. In addition to pres- ence of del(17p), seven patients who progressed had an unmutated IGHV locus. Karyotype analysis was available for eight patients who had progressed, of whom two had complex karyotype (number of abnormalities: 5 and 6). Four patients had histologically confirmed transformation to aggressive lymphoma, while two patients had suspect- ed transformation. The present results compare favorably to those reported with chemoimmunotherapy, where 23% of patients with del(17p) treated in the first line expe- rienced disease transformation, with a median time to transformation of 12 months.41 In the RESONATE-17 trial of R/R CLL patients, 44% of progression events were due to transformation, most within the first 6 months of treat- ment.10 Similarly, both early progression events in the TN del(17p) or TP53 populations treated with ibrutinib, as reported by Farooqi and colleagues, occurred due to Richter transformation.37 These data are in line with the known association of del(17p) and transformation to aggressive lymphomas.42 Long term outcomes for patients with del(17p) treated with ibrutinib were reported by Ahn and colleagues,38 showing an approximate 5-year PFS of 75%. Further follow-up will be required to demonstrate the durability of responses to zanubrutinib. Additional analyses, including correlation of response and progres- sion with concurrent genomic abnormalities and other genetic mutations (e.g., TP53, NOTCH1, BTK, and PLCG2 mutations), both at baseline and at the time of progres- sion, are currently in progress.
The clinically meaningful activity noted in this patient series appears to be associated with a favorable toxicity profile and is consistent with that reported in other studies of zanubrutinib to date.20,43 Despite enrolling a more eld- erly and comorbid population and allowing for therapeu- tic anticoagulation on study, the incidence of grade ≥3 AE or SAE leading to major bleeding was 5.6% with no CNS events reported, and all patients able to continue study
drug after dose interruption. Consistent with its greater selectivity for BTK and less inhibition of kinases such as EGFR, Src, and others, the incidence of grade 3 AE such as diarrhea, arthralgia, and myalgia were all ≤1%. Importantly, only three patients on this study reported treatment-emergent atrial fibrillation, six patients required ongoing dose reduction, and four patients discontinued zanubrutinib due to an AE. Two phase III randomized studies in patients with R/R CLL/SLL44 and Waldenström macroglobulinemia45 are ongoing to directly compare the efficacy and safety profiles of ibrutinib and zanubrutinib.
Limitations of this study include the relatively short duration of follow-up and its single-arm design. A retro- spective analysis for baseline TP53 mutations is currently being performed for this study arm and the larger random- ized arms. Analogous to other BTK inhibitors, the single- agent activity of zanubrutinib is not expected to induce a deep response with eradication of minimal residual dis- ease (MRD). Several studies have recently reported achievement of undetectable MRD in patients with TN CLL/SLL, including those patients with del(17p), by com- bining a BTK inhibitor with obinutuzumab or veneto- clax.36,46,47 The SEQUOIA trial is currently enrolling patients in Arm D, which will evaluate the safety and activity of a combination of zanubrutinib with venetoclax in TN CLL/SLL patients with del(17p). In summary, these results indicate that single-agent zanubrutinib is active and generally well tolerated in this very high-risk population.
Disclosures
CST received research funding from Janssen, AbbVie, BeiGene, Pharmacyclics, TG Therapeutics and AbbVie and served as a consultant for BeiGene, Janssen, Roche, AbbVie and Loxo; TR served as a consultant for and received honoraria and research funding from Gilead; PG served as a consultant for Adaptive, AbbVie, ArQule, BeiGene, Celgene/Juno, Dynamo, Gilead, Janssen, Sunesis and received research funding from AbbVie, Gilead, Janssen, Novartis, and Sunesis; LL received honoraria from Roche and AbbVie, and served as a consultant for BeiGene, Roche, AbbVie, AstraZeneca, Janssen, and Gilead; BSK served as a consultant for AbbVie, Acerta, AstraZeneca, BeiGene, Janssen and Pharmacyclics; PW is an employee of Alfred Health (public hospital) and Peninsula Health (public hos- pital) and received travel funding from Roche; WJ served as a con- sultant for AstraZeneca and served on advisory boards for Janssen, Celgene, and Amgen; DS is an employee of and has equity ownership in BeiGene, received honoraria from AbbVie, Janssen, and Roche, received research funding from AbbVie, Amgen, Celgene, Roche, MSD, Acerta, Pharmacyclics, Sanofi, and GSK; MS served as a consultant for AbbVie, Genentech, AstraZeneca, Pharmacyclics, Verastem, ADC Therapeutics, Atara Biotherapeutics, Cellectar, and Bristol Myers Squibb, and received research funding from Mustang Bio, Celgene, Pharmacyclics, Gilead and Genentech, TG Therapeutics, BeiGene, AstraZeneca, Sunesis, Acerta Pharma, Atara Biotherapeutics, and Bristol Myers Squibb; SO received honorar- ia from and served as a consultant for AbbVie, Roche, AstraZeneca, Merck, Gilead, Janssen, and Novartis, received research funding from BeiGene, Roche, AstraZeneca, Janssen, Merck, Amgen, and Epizyme, and received travel funding from Roche; MT has nothing to disclose; HC is an employee of Copernicus Wojewódzkie Centrum Onkologii Gdańsk; EV received research funding from Janssen; MŠ served as a consult- ant for and received travel expenses from AbbVie, Gilead, Janssen-Cilag, and Acerta, and served on an advisory board for
haematologica | 2021; 106(9)
2361