The impact of early venetoclax discontinuation or dose modification on outcomes of patients with R/R CLL

March 2022 Clinical practice Andrea Enguita

Thus far, there was limited information on the impact of premature venetoclax discontinuation and/or treatment modification on the survival outcomes of patients with relapsed or refractory chronic lymphocytic leukaemia (R/R CLL). A post-hoc analysis of the MURANO trial now demonstrates that venetoclax treatment discontinuation is associated with poor outcomes for the patients, while temporal interruptions or dose modifications have no significant impact.

EXPERT OPINION OF PROF. DR. DOMINIQUE BRON, HAEMATOLOGIST, INSTITUT JULES BORDET

“Dose reductions were required by 45 of 194 (23%) patients, but had no significant impact on outcomes. In MURANO, premature discontinuation was associated with suboptimal outcomes; venetoclax treatment modification was not. These data highlight the importance of effective toxicity control to realise the full benefit of venetoclax treatment.”

Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia in Western countries. Novel targeted therapies have improved outcomes over chemo-immunotherapy in first-line and relapsed/refractory (R/R) CLL. These comprise selective kinase inhibitors targeting the B-cell receptor and its downstream proteins, and the potent B-cell lymphoma-2 (BCL-2) inhibitor venetoclax.  Although targeted therapies have manageable safety profiles, both premature discontinuations and therapy modifications are reported in a proportion of cases. Thus far, there is limited information about the impact of venetoclax premature discontinuation and/or treatment modification on the survival outcomes of patients with CLL. The phase III MURANO study evaluated the efficacy of venetoclax in combination with rituximab (VenR) compared to bendamustine plus rituximab (BR), in patients with R/R CLL. A post-hoc analysis of MURANO now assessed the impact of venetoclax discontinuation/modification on the patient outcomes.

STUDY DESIGN

Analyses were performed on data from the VenR cohort in the MURANO study (N= 194).  Participants received venetoclax over a 5-week dose ramp-up period (to reach the 400 mg daily target dose) followed by six cycles of rituximab with ongoing daily dosing of venetoclax. Patients continued daily venetoclax therapy for a maximum of two years. Time-dependent Cox proportional hazards regression models, stratified by 17p deletion and risk status, evaluated the impact of venetoclax discontinuation/ modification on investigator-assessed progression-free survival (PFS) and overall survival (OS). Analyses were performed retrospectively (without type-1 error control) in intention-to-treat patients from the VenR arm of MURANO.

RESULTS

Overall, 72% of the patients in the VenR arm completed two years of therapy while 28% prematurely discontinued treatment. The two most common reasons for discontinuation were adverse events (AEs, 53.7%), followed by disease progression (PD, 22.2%). In total, 79% of the reported deaths (N= 28) were patients who prematurely discontinued venetoclax.

Early discontinuation of the treatment (for any reason except PD) was significantly associated with shorter PFS (N= 181; HR[95%CI]: 5.98[3.31–10.82]; p< 0.0001). A similar adverse impact on PFS was observed for patients who discontinued treatment due to an AE (N= 174; HR[95%CI]: 5.82[2.93–11.57]; p< 0.0001).  This inferior survival was consistent with treatment discontinuation due to venetoclax-related AE (N= 174; HR[95%CI]: 2.34[1.10–4.98]; p= 0.0272). Risk of a PFS/OS event was significantly reduced by each extra month (exposure cycle) of venetoclax therapy (p= 0.0263 for PFS; p< 0.0001 for OS). Overall, 134 patients (69.1%) required treatment interruption for AE. The most common types of AE leading to treatment interruption were blood and lymphatic system disorders (49.0%), infections and infestations (24.2%), gastrointestinal disorders (8.2%) and investigations (7.7%). Of the 194 patients receiving VenR, 70.6% required a total of 316 interruptions to venetoclax treatment. Most of the interruptions (212 of 316) occurred during the combination treatment phase, with 60.3% interrupting treatment during combination therapy versus 32.0% with interruptions during the monotherapy treatment phase. The median consecutive days duration of treatment interruption was 9 days. Treatment interruption, regardless of duration (≥1, ≥8, ≥14 and ≥21 consecutive days of missed venetoclax treatment) had no statistically significant effect on PFS or OS compared with no treatment interruption.

 Of the 194 patients receiving VenR, 23.2% required dose reductions for venetoclax. A total of 76 dose reductions were required, with some patients having multiple dose reductions. Dose reduction had no statistically significant effect on PFS (p= 0.5765) or OS (p= 08519) compared with patients with no dose reduction.

CONCLUSION

Treatment discontinuation prior to completing the MURANO regimen (fixe duration of two years of venetoclax) was associated with impaired PFS, while improved PFS and OS were associated with greater cumulative venetoclax treatment exposure. PFS was also statistically significantly lower with discontinuation specifically due to AE. Temporal treatment interruption or dose reduction had no impact on the patient outcomes, highlighting the importance of management of AE to allow alternative options such as dose modification or re-initiation of therapy following a treatment break, to maximise the duration of therapy.

Reference

Mato AR, Sharman JP, Biondo JM, et al. The impact of early discontinuation/dose modification of venetoclax on outcomes in patients with relapsed/refractory chronic lymphocytic leukemia: post-hoc analyses from the phase III MURANO study. Haematologica. 2022;107(1): 134-42.

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