Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables

Abstract

To define the efficacy of venetoclax with extended follow-up and identify clinical or biological treatment effect modifiers, updated data for previously treated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) enrolled in 4 early-phase trials were pooled. Rates of response, complete remission (CR/CRi), and undetectable minimal residual disease (U-MRD) were analyzed for all patients (n = 436) and for those patients who were planned to receive 400 mg/day monotherapy (n = 347). Univariate and multiple regression analyses were performed to identify the pretreatment factors associated with response rates and duration of response (DoR). Objective responses were documented in 75% of all patients, including 22% CR/CRi. Overall, 27% and 16% of the patients achieved U-MRD in blood and marrow, respectively. Estimated median progression-free survival (PFS), DoR, and time to progression were 30.2, 38.4, and 36.9 months, respectively. Similar efficacy outcomes were observed within the 400 mg/day monotherapy subset. For those who achieved CR/CRi, the 3-year PFS estimate was 83%. DoR was superior for patients achieving CR/CRi or U-MRD in landmark analyses. In multiple regression analyses, bulky lymphadenopathy (≥5 cm) and refractoriness to B-cell receptor inhibitor (BCRi) therapy were significantly associated with lower CR rate and shorter DoR. Fewer prior therapies were associated with higher CR rate, but not DoR. Chromosome 17p deletion and/or TP53 mutation and NOTCH1 mutation were consistently associated with shorter DoR, but not probability of response. Thus, both pretreatment factors and depth of response correlated with DoR with venetoclax. Patients without bulky lymphadenopathy, BCRi-refractory CLL, or an adverse mutation profile had the most durable benefit.

The efficacy and safety of venetoclax therapy in elderly patients with relapsed, refractory chronic lymphocytic leukaemia

“…Progression‐free survival (PFS) across a recent pooled analysis of early‐phase trials ( n = 436) was c . 30 months (Roberts et al, ) but was dependent on patient and disease characteristics. The median age was 66 years (Roberts et al, ) across all patients with those ≥70 years achieving similar response depth, duration and minimal residual disease negativity compared to younger patients.…”

“…Phase II trials demonstrate impressive activity in these settings with an overall response rate (ORR) of c. 80% in the B-cell receptor inhibitor (BCRi)-na€ ıve setting (Stilgenbauer et al, 2016) and high response rates (65-67%) post-BCRi (Jones et al, 2017;Coutre et al, 2018). Progression-free survival (PFS) across a recent pooled analysis of early-phase trials (n = 436) was c. 30 months (Roberts et al, 2019) but was dependent on patient and disease characteristics. The median age was 66 years (Roberts et al, 2019) across all patients with those ≥70 years achieving similar response depth, duration and minimal residual disease negativity compared to younger patients.…”

“…Progression-free survival (PFS) across a recent pooled analysis of early-phase trials (n = 436) was c. 30 months (Roberts et al, 2019) but was dependent on patient and disease characteristics. The median age was 66 years (Roberts et al, 2019) across all patients with those ≥70 years achieving similar response depth, duration and minimal residual disease negativity compared to younger patients. AE rates, including grade (G) 3/4 AEs, serious AEs, and AEs leading to venetoclax dose reduction, interruption, or discontinuation did not differ according to age (<75 or ≥75 years) within a pooled analysis of 350 venetoclax-treated trial patients .…”

Ibrutinib in the treatment of chronic lymphocytic leukemia: 5 years on

“…This suggests that venetoclax should be part of next‐generation fixed duration combination therapy possibly MRD‐driven. Since ibrutinib and venetoclax have a complementary compartmental activity in CLL (ibrutinib on lymph node and venetoclax on peripheral blood and bone marrow) association of these agents appears particularly useful for younger patients and those with high‐risk molecular characteristics . However, also using the association of ibrutinib and venetoclax we do not know as yet if any of these patients are cured.…”

“…Since ibrutinib and venetoclax have a complementary compartmental activity in CLL (ibrutinib on lymph node and venetoclax on peripheral blood and bone marrow) association of these agents appears particularly useful for younger patients and those with high-risk molecular characteristics. 65,66 However, also using the association of ibrutinib and venetoclax we do not know as yet if any of these patients are cured. In this population, we are hopeful that using novel agents in combination and continued improvements in chimeric antigen receptor (CAR) T-cell therapy approaches will provide better results.…”