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Sustained progression-free and overall survival benefit of time-limited venetoclax-rituximab over bendamustine-rituximab in relapsed/refractory CLL

The phase III MURANO trial previously established that fixed duration venetoclax plus rituximab (VenR) resulted into a significantly longer progression-free survival (PFS) and overall survival (OS) compared to bendamustine-rituximab in patients with relapsed/refractory chronic lymphocytic leukemia. During ASH 2019, four-year follow-up data of this trial was presented and this confirmed the sustained benefit of VenR over BR. Also the off-treatment PFS for patients treated with VenR was sustained with a 24-months post treatment PFS rate of 68%. In addition to this, the updated analysis clearly showed that undetectable minimal residual disease at the end of treatment is associated with a longer PFS. Interestingly, the researchers also demonstrated that salvage therapy with either ibrutinib or venetoclax was feasible after disease progression on VenR.

Background

In the phase III MURANO trial, fixed-duration venetoclax plus rituximab (VenR) was compared to bendamustine-rituximab (BR) in 389 patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL). Patients were randomly assigned to be treated following two different regimes. In the first regime, 6 cycles of VenR were administered, with venetoclax in a 5-week ramp up from 20 to 400 mg per day, then 400 mg once daily. Rituximab was administered 375 mg/m2 on day 1 of cycle 1 then 500 mg/m2 on day 1 of cycles 2-6. This was followed by 400 mg Ven monotherapy once daily for a maximum of 2 years (measured from day 1 of cycle 1). The other regime consisted of 6 cycles of BR. Bendamustine was administered in doses of 70 mg/m2 on days 1 and 2 of cycles 1-6 and rituximab in doses of 375 mg/m2 on day 1 of cycle 1, and then 500 mg/m2 on day 1 of cycles 2-6. After a median follow-up of 36 months, both the PFS (HR 0.16 [95% CI: 0.12-0.23]; p<0.001) and OS (HR 0.50 [95% CI: 0.30-0.85]; p=0.0093) were reported to be significantly better with VenR than with BR. After a median of 9.9 months off therapy, the 3-year PFS estimates were 71.4% and 15.2% for VenR and BR, respectively. In this previous analysis, the 3-year OS rates were 87.9% for VenR as compared to 79.5% for BR. The study treatment was given in second line in approximately 60% of patents, while 25% and 15% of patients received it in third and fourth line, respectively. During ASH 2019, an updated analysis of this trial was presented with a median follow-up of 48 months.

Results

The PFS benefit with VenR over BR was sustained 2 years after the EOT, with 57.3% of VenR patients being alive and free of progression at four years, as compared to only 4.6% with BR (HR 0.19 [95% CI: 0.14-0.25]; p<0.0001). The 24-months post-treatment cessation PFS estimate in VenR patients who completed 2 years of Ven (N=130) was 68%. With a median of 22 months off therapy, 35 progression events had occurred in the 130 patients who completed 2 years of Ven. A closer look into these progressions learns that the chance of having disease progression was lowest in patients with undetectable minimal residual disease (uMRD) at the end of treatment (EOT, progressive disease in 13.3% as compared to 39.1% and 92.9% in patients with low- and high-MRD-positivity at the EOT, respectively). At 18-months, 90.3% of VenR-treated patients with uMRD at the EOT were alive and free of progression, while this was only the case in 64.4% and 8.3% of patients with low- or high-MRD+ at the EOT, respectively (uMRD vs. low-MRD+: HR 0.25 [95% CI: 0.1-0.64]; p=0.002; uMRD vs. high-MRD+: HR 0.03 [95% CI: 0.01-0.09]; p<0.0001). Of note, patients with a high-MRD+ status at the EOT already had a rising MRD before treatment cessation, indicating that longer treatment continuation would probably not have avoided the disease relapse.

Likewise, the OS benefit of VenR over BR was maintained in this updated analysis, despite the fact that a high proportion of patients in the BR arm received novel targeted therapies after a disease relapse (4-year OS rate: 85.3 vs. 66.8%; HR 0.42 [95% CI: 0.26-0.65]; p<0.0001). In total, 28 patients with disease progression on VenR were evaluable for response on subsequent therapy. Among these patients, an overall response rate (ORR) of 64.3% was reported. The response rates to subsequent ibrutinib or venetoclax were 100% (10/10) and 55% (6/11), respectively. No new safety signals were observed with this longer follow-up.

Conclusions

After a median follow-up of 48 months, the PFS and OS benefits of time-limited VenR over BR were sustained. After 22 months of post-treatment follow-up, the 24-months PFS estimate was 68%. In addition to this, obtaining uMRD at the EOT with VenR proved to be strongly associated with a prolonged PFS. The continued widening of the OS curves in this trial, despite the majority of BR patients progressing and receiving effective salvage therapies, indicates the value of using VenR early in the disease course. Finally, data on subsequent therapy indicate that salvage therapies post VenR, including ibrutinib and Ven, are still effective.

Reference

Seymour J, et al. Four-Year Analysis of Murano Study Confirms Sustained Benefit of Time-Limited Venetoclax-Rituximab (VenR) in Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL). Presented at ASH 2019; Abstract 355.

Speaker John F. Seymour

Seymour

John F. Seymour, MBBS, PhD, FRACP, Royal Melbourne Hospital, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Australia

 

See: Keyslides

 

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