Alessandra Tedeschi, MD, discusses outcomes with zanubrutinib plus venetoclax in patients with CLL/SLL harboring deletion 17p and/or TP53 mutations. L

Dr Tedeschi on the Initial Efficacy of Zanubrutinib Plus Venetoclax in Del 17p/TP53–Mutant CLL/SLL

Alessandra Tedeschi, MD, consultant, hematology, Department of Hematology, Niguarda Hospital, Milan, Italy, discusses preliminary results from arm D of the phase 3 SEQUOIA trial (NCT03336333) investigating zanubrutinib (Brukinsa) plus venetoclax (Venclexta) in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) harboring deletion 17p and/or 

Findings from this cohort were presented at the 

, and showed deep and durable responses with the combination among response-evaluable patients in this high-risk population (n = 65), Tedeschi reports. The overall response rate reached 100%, with 48% of patients experiencing either a complete response (CR) or CR with incomplete hematopoietic recovery, she details. Additionally, 59% of patients achieved undetectable minimal residual disease in at least 1 peripheral blood sample at a median follow-up of 31.6 months. The median progression-free survival (PFS) was not reached, but the 12-month and 24-month PFS estimates were 95% and 94%, respectively.

The safety profile of the combination remained consistent with that of its individual components, with no new safety signals identified, Tedeschi continues. Common all-grade non-hematologic treatment-emergent adverse effects (TEAEs) included infections (71%), COVID-19 (55%), diarrhea (39%), nausea (30%), and contusions (29%). Grade 3 or higher non-hematologic TEAEs were observed in 44% of patients, with infections (15%), diarrhea (9%), hypertension (8%), and second primary malignancies (8%) being the most frequent. Hematologic toxicity primarily involved neutropenia, which occurred in 22% of patients overall and 17% at grade 3 or higher. Notably, the proportion of patients at high risk for tumor lysis syndrome (TLS) decreased significantly from 35% at screening to 3% after three cycles of lead-in zanubrutinib, and no TLS cases were reported. Although neutropenia was slightly higher, this was expected given the combination of therapies and did not correlate with an excess of infections.

Compared with the current standard of ibrutinib (Imbruvica) and venetoclax, the addition of the next-generation BTK inhibitor zanubrutinib to venetoclax confers a better safety profile and deeper, prolonged responses, she concludes.

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Alessandra Tedeschi, MD, discusses the utility of zanubrutinib plus venetoclax in patients with CLL/SLL harboring deletion 17p and/or TP53 mutations.

Dr Tedeschi on Long-Term Data With First-Line Ibrutinib in CLL

Alessandra Tedeschi, MD, consultant, hematology, Department of Hematology, Niguarda Hospital, Milan, Italy, discusses 10-year follow-up data from the phase 3 RESONATE-2 trial (NCT01722487) investigating first-line ibrutinib (Imbruvica) in treatment-naive chronic lymphocytic leukemia (CLL).

The international, multicentre, open-label, trial compared ibrutinib monotherapy with chlorambucil in 269 patients with previously untreated CLL or small lymphocytic leukemia who were aged 65 years or older, Tedeschi begins.

Long-term follow-up data from the RESONATE-2 study were presented at the 

and confirmed that ibrutinib produced and sustained improvements in progression-free survival (PFS) vs chlorambucil for patients with CLL in the first line, she reports. At a median follow-up of 10 years, the median PFS was 8.9 years in the ibrutinib arm vs 1.3 years in the chlorambucil arm (HR, 0.16; 95% CI, 0.11–0.22; 

 < 0.0001). PFS benefit was noted across all subgroups, including those with high-risk genomic features such as 

 mutations, unmutated IGHV, or 11q deletions. In these high-risk groups, the HR was 0.09 (95% CI, 0.05–0.15; 

 < 0.0001), underscoring the broad applicability of ibrutinib in various patient populations.

The study also showed that the median overall survival (OS) had not been reached for patients treated with ibrutinib after up to 10 years of follow-up. At 9 years, the OS rate was 68% (95% CI, 58.6–75.7). Notably, 27% of patients remained on ibrutinib after 10 years, with a median duration of treatment of 6.2 years (range, 0.06-10.2). These findings illustrate the durability of response and the potential for long-term disease control with ibrutinib.

Regarding safety, long-term treatment with ibrutinib was well tolerated, with no new safety signals emerging over the course of the study, Tedeschi continues. The most significant adverse effects (AEs) occurred during the first year of treatment. In the later years of follow-up, the rates of AEs of interest were relatively low. During years 8 to 9 and 9 to 10, hypertension was reported in 28% (n=15) and 26% (n=11) of patients, respectively, while atrial fibrillation was reported in 8% (n=4) and 9% (n=4) of patients, respectively.

This study is particularly noteworthy as it represents the longest follow-up ever reported for a BTK inhibitor in treatment-naive CLL, Tedeschi emphasizes. The sustained efficacy and manageable safety profile of ibrutinib over a decade highlight its role as a cornerstone in the first-line treatment of CLL, especially for patients with high-risk genomic features.

Alessandra Tedeschi, MD, discusses 10-year follow-up data on treatment with first-line ibrutinib in treatment-naive chronic lymphocytic leukemia.

Alessandra Tedeschi MD, Department of Hematology, Azienda Ospedaliera Niguarda Ca' Granda in Milan, Italy, discusses the long-term findings of the phase III RESONATE-2 trial during the 2019 European Hematology Association Congress.

Ibrutinib, a once-daily BTK inhibitor, is approved for the frontline treatment of patients with chronic lymphocytic leukemia (CLL). The RESONATE-2 study, a phase III open-label trial, compared the efficacy and safety of the agent in the first-line setting versus chlorambucil in older patients, aged 65 years or older, with CLL.

The study demonstrated that ibrutinib, used as a single agent, had sustained benefit in terms of overall survival (OS) and progression-free survival (PFS), even for patients who had high-risk genomic features. Responses to the agent improved over time. With 66 months of follow-up, more than half of the 269 patients enrolled remain on treatment.

According to Tedeschi, treating older patients with CLL has always been a challenge, because many patients are unfit, and they may have comorbidities or intolerance to immunotherapy. Ibrutinib has provided a useful, more easily tolerated treatment option that has performed well in this patient population in terms of PFS and OS.

2019 European Hematology Association Congress

Alessandra Tedeschi MD

Articles

Dr Tedeschi on the Initial Efficacy of Zanubrutinib Plus Venetoclax in Del 17p/TP53–Mutant CLL/SLL

Dr Tedeschi on Long-Term Data With First-Line Ibrutinib in CLL

Dr. Tedeschi on Frontline Ibrutinib for Older Patients With CLL