Venetoclax/Rituximab Maintains PFS Advantage With uMRD in Relapsed/Refractory CLL

A fixed-duration of venetoclax (Venclexta) plus rituximab (Rituxan) led to sustained and durable responses in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who achieved undetectable minimal residual disease (uMRD), according to findings from the 4-year analysis of the phase 3 MURANO trial.¹

The 4-year analysis, which was published in the Journal of Clinical Oncology, demonstrated a progression-free survival (PFS) rate of 57.3% with the combination versus 4.6% with bendamustine plus rituximab (BR; HR, 0.19; 95% CI, 0.14-0.25). The overall survival (OS) rate was also improved, at 85.3% with the combination versus 66.8% with BR (HR, 0.41; 95% CI, 0.26-0.65).

Patients who achieved uMRD had the most favorable outcome in both arms. With venetoclax/rituximab, the HR for PFS was 0.50 (95% CI, 0.28-0.89; P = .02) in patients with low uMRD versus 0.15 (95% CI, 0.06-0.36; P < .0001) in patients with high MRD positivity. The HR was 0.25 in patients with high MRD positivity versus those with low MRD positivity (95% CI, 0.10-0.66; P = .002).

Additionally, the analysis evaluated the impact of genomic complexity (GC) and genetic mutations on patient outcomes. Patients with GC had a lower rate of uMRD at the end of treatment with venetoclax/rituximab compared with those patients who lacked GC (P = .042). Patients with higher GC had shorter PFS versus patients with lower GC.

Patients whose tumors harbored BIRC3 or BRAF mutations had higher rates of MRD positivity at the end of treatment with the fixed-dose combination. Patients with TP53, NOTCH1, XPO1, and BRAF mutations had higher rates of MRD positivity at the end of treatment overall.

CLL remains a largely incurable disease despite therapeutic advances and favorable OS rates with BR. Additionally, BR and other regimens, such as BTK inhibitors, do not offer curative potential, which results in an increased risk of developing resistance mutations upon progression. As such, fixed-duration therapies, such as the combination of venetoclax and rituximab, offer the potential to limit resistant mutation development, reduce toxicity, and alleviate financial burden.

The MURANO trial randomized 389 patients with relapsed/refractory CLL to receive 6, 28-day cycles of venetoclax/rituximab, followed by 400 mg of venetoclax once daily for a total of 2 years (n = 194), or 6, 28-day cycles of BR, given at the standard dose (n = 195).

Patient characteristics were similar between arms.² Eligible patients were 18 years of age or older with relapsed/refractory CLL. Patients had to have received 1 to 3 previous treatments, including at least 1 chemotherapy-containing regimen. Additionally, all patients had to have an ECOG performance score of 0 or 1, as well as adequate bone marrow, renal, and hepatic function.

Patients may have received prior bendamustine, provided that they stopped bendamustine at least 24 months prior to enrollment.

Patients were stratified based on the presence or absence of 17p deletions, responsiveness to previous therapy, and geographic region.

Of the 288 patients with GC data, 67.3% had non-complex status, meaning they harbored 0 to 2 aberrations. Moreover, 21.9% had low GC with 3 to 4 aberrations, and 10.8% had high GC with 5 or more aberrations. High GC and low GC status was associated with an increased frequency of high MRD positivity at the end of treatment (P = .042).

The OS benefit with venetoclax/rituximab was observed despite the majority (79%) of patients in the BR arm having received targeted agents after progression. These agents included BTK inhibitors (n = 60), PI3K inhibitors (n = 9), venetoclax (n = 10), or other investigational medicinal products (n = 2). In the venetoclax/rituximab arm, 67% of patients who experienced progression received novel agents, including BTK inhibitors (n = 12), PI3K inhibitors (n = 1), reexposure to venetoclax (n = 14), or other investigational medicinal products (n = 1).

Of the 12 patients who received the BTK inhibitor ibrutinib (Imbruvica) after venetoclax, the response rate was 100% among evaluable patients (n = 10). At a follow-up time ranging from 6.2 to 42.9 months, 8 patients were still receiving ibrutinib. Three patients experienced progressive disease, leading to 2 fatalities.

Fourteen patients were treated with a venetoclax-based regimen following treatment with venetoclax. Of 11 evaluable patients, the response rate was 55%. Two patients achieved stable disease, 1 did not respond, and 3 experienced disease progression.

At a median of 22 months off therapy, 73.1% of patients who received the investigational combination remained progression free following 2 years of venetoclax.​

In patients who achieved a complete response (CR) or a CR with incomplete marrow recovery, MRD status did not appear to influence PFS and all patients had uMRD (n = 33) or low MRD positivity (n = 8).

The study demonstrated an 83.5% concordance between detection of 17p deletion by clinically applied array comparative genomic hybridization and the fluorescence in situ hybridization assay by central laboratory testing.

At baseline, major genomic aberrations included 13q14 monoallelic deletions (44.4%), 11q22.3 deletions (31.7%), 13q14 biallelic deletions (16.9%), 17p13.1 deletions (12%), and trisomy 12 mutations (9.9%). Most patients who received venetoclax/rituximab had multiple abnormalities.

The 4-year analysis did not highlight any new safety signals with the combination. Three patients developed additional second primary malignancies since the prior analysis, excluding nonmelanoma skin malignancies. Of these malignancies, 1 patient treated with BR developed melanoma, and 2 patients treated with venetoclax/rituximab developed melanoma and breast cancer (n = 1 each). The safety results did not show any new reports of Richter transformation.

According to the study investigators, these data further support the use of the fixed-duration combination of venetoclax and rituximab in patients with relapsed/refractory CLL.

References

1. Kater AP, Wu JQ, Kipps T, et al. Venetoclax plus rituximab in relapsed chronic lymphocytic leukemia: 4-year results and evaluation of the impact of genomic complexity and gene mutations from the MURANO phase III study. J Clin Oncol. Published online September 28, 2020. doi:10.1200/JCO.20.00948
2. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax–rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120. doi:10.1056/NEJMoa1713976