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Zanubrutinib improves progression-free survival in relapsed lymphocytic leukaemia

Rod Tucker
21 December, 2022  

Zanubrutinib was superior to ibrutinib in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma

In a head-to-head trial, zanubrutinib provided superior progression-free survival compared to ibrutinib in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, according the the results to a study by team of international researchers.

Chronic lymphocytic leukaemia (CLL) is an adult leukaemia characterised by abnormal accumulation of immunologically incompetent lymphocytes in blood, bone marrow, lymph nodes, and spleen and accounts for 25–30% of all leukaemias in Western Countries, leading to over 100,000 incident cases with more than 40,000 global deaths reported in 2019. In contrast, small lymphocytic lymphoma (SLL) comprises approximately 7% of newly-diagnosed cases of non-Hodgkin’s lymphomas although often at the time of diagnosis, most patients present with advanced-stage disease including generalised lymphadenopathy, hepatosplenomegaly and bone marrow involvement.

Bruton’s tyrosine kinase (BTK) is a non-receptor kinase that plays a crucial role in oncogenic signalling and which is critical for proliferation and survival of leukaemia cells in many B cell malignancies. Moreover, oral irreversible BTK inhibitors such as ibrutinib, have been shown to provide a high response rates in patients with relapsed/refractory CLL and mantle-cell lymphoma. Zanubrutinib is a highly selective Bruton tyrosine kinase inhibitor that is well tolerated and demonstrated activity in patients with relapsed/refractory mantle cell lymphoma. In a multinational, phase 3, randomised trial, the same international research group, performed a head-to-head comparison of zanubrutinib with ibrutinib as treatment for relapsed or refractory CLL or small lymphocytic lymphoma (SLL). At a pre-specified interim analysis, the results showed that zanubrutinib provided a significantly higher overall response rate, lower atrial fibrillation rate and improved progression-free survival compared to ibrutinib after 15 months. In the current study, researchers provided an update on progression-free survival after nearly 30 months. In the trial, participants with relapsed or refractory CLL or SLL and who had received at least one previous course of therapy, were randomised 1:1 receive zanubrutinib at a dose of 160 mg twice daily or ibrutinib at a dose of 420 mg daily until the occurrence of disease progression or unacceptable toxic effects.

Zanubrutinib and progression-free survival

A total of 652 patients with a median age of 67 years (68.3% male) were included and randomised to zanubrutinib (327) or ibrutinib and followed for a median of 29.6 months.

In terms of progression-free survival, zanubrutinib was superior for disease progression or death with 87 vs. 118 occurrences of disease progression or death (hazard ratio, HR = 0.65, 95% CI 0.49 – 0.86, p = 0.002). At 24 months, the investigator-assessed rates of progression-free survival were 78.4% in the zanubrutinib group and 65.9% in the ibrutinib group.

Furthermore, the safety profile of zanubrutinib was better than ibrutinib, with fewer adverse events leading to treatment discontinuation and fewer cardiac events, including fewer cardiac events leading to treatment discontinuation or death.

The authors concluded that among those with relapsed or refractory CLL or SLL, progression-free survival was significantly longer among patients who received zanubrutinib and that the drug was associated with fewer cardiac adverse events.

Citation
Brown JR et al. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med 2022