Venetoclax/Rituximab Retreatment Produces Durable Responses in CLL

Retreatment with venetoclax (Venclexta) plus rituximab (Rituxan) generated responses in 100% of patients with chronic lymphocytic leukemia (CLL) who had previously achieved a deep response with initial treatment with venetoclax plus rituximab, discontinued treatment, and developed progressive disease (PD), according to findings from the phase 1b M13-365 trial (NCT01682616) presented at the 2024 EHA Congress.¹

All 9 patients included in this analysis achieved either a complete response (CR; n = 6), CR with incomplete hematologic recovery (CRi; n = 2), or partial response (PR; n = 1) after initial therapy. Subsequently, all 9 patients experienced either a CR (n = 3) or PR (n = 6) after retreatment. Among these patients, 78% and 22% achieved undetectable minimal residual disease (MRD) after initial therapy and after retreatment, respectively.

“Determining the effectiveness of retreatment with venetoclax plus rituximab is of great interest [for] patients with CLL who achieved an initial deep response followed by PD after initial venetoclax plus rituximab treatment,” Danielle M. Brander, MD, and coauthors, wrote in a poster of the data.

Brander is an associate professor of medicine, hematologic malignancies, and cellular therapy, and is a member of the Duke Cancer Institute in Durham, North Carolina.

Outlining the Rationale for Retreatment

Findings from the phase 3 MURANO trial (NCT02005471) demonstrated that treatment with the combination of venetoclax plus rituximab for a maximum of 2 years resulted in durable remissions in patients with relapsed/refractory CLL/small lymphocytic lymphoma (SLL) that were sustained off treatment.2 At a median follow-up of 7 years, the median progression-free survival (PFS) was 54.7 months (95% CI, 52.3-59.9) with venetoclax plus rituximab (n = 194) vs 17.0 months (95% CI, 15.5-21.7) with bendamustine plus rituximab (n = 195; HR, 0.25).

Furthermore, among patients with relapsed/refractory CLL enrolled in the MURANO trial who were retreated with venetoclax plus rituximab (n = 25), the best overall response rate to retreatment was 72.0%, and these patients achieved a median PFS of 23.3 months (95% CI, 15.6-24.3).

Diving into the Design of M13-365

The open-label, multicenter M13-365 trial enrolled patients at least 18 years of age with relapsed/refractory CLL or SLL who had an ECOG performance status of 0 or 1 and had received up to 3 prior lines of myelosuppressive regimens.¹ Following dose-escalation and -expansion/safety portions, 49 patients received oral venetoclax at 400 mg daily in combination with intravenous rituximab at 375 mg/m2 starting on day 1 of week 6, then at 500 mg/m2 once per month for 5 months. Thirty-three patients who achieved CR/CRi or PR with undetectable MRD met the criteria for deep response and had the option to stop treatment. Of these patients, 16 elected to stop treatment. Nine of those patients were retreated with venetoclax plus rituximab after experiencing PD off therapy and were included in this retreatment analysis.

Among the 9 retreated patients, the median age was 66 years (range, 58-79), and 44% were male. Among assessed patients (n = 5), none had acquired BCL-2 mutations at the time of retreatment. Patients had received a median of 2 prior treatments (range, 1-4). Genomic features included 17p deletions (n = 1), TP53 mutations (n = 1), and unmutated IGHV (n = 5).

Reporting Further Data from M13-365

Previously, the M13-365 trial showed that rituximab in combination with fixed-duration or continuous venetoclax induced deep and durable responses in patients with CLL. Among responders, 74% maintained their response for at least 5 years. The median duration of initial treatment with venetoclax was 0.8 years (range, 0.4-3.3), which translated to 9.2 months (range, 4.6-39.8).

The median time off treatment before PD was 3.2 years (range, 1.4-5.7), which translated to 38.4 months (range, 17.3-68.7). The median time from PD to retreatment with venetoclax plus rituximab was 0.4 years (range, 0.04-3.0), which translated to 4.9 months (range, 0.5-35.5).

Following initial treatment, the median PFS was 9.5 years (95% CI, 4.2–not evaluable [NE]), which translated to 114.5 months (95% CI, 50.9-NE). The 24-, 48-, and 60-month PFS rates were 100% (95% CI, 100%-100%), 100% (95% CI, 100%-100%), and 86.3% (95% CI, 43.3%-86.4%), respectively.

Following retreatment, the median PFS was 4.9 years (95% CI, 1.6-NE), which translated to 58.7 months (95% CI, 18.7-NE). The 24-, 48-, and 60-month PFS rates were 86.9% (95% CI, 43.3%-88.4%), 50.8% (95% CI, 15.7%-78.1%), and not assessed, respectively.

The median overall survival (OS) from initial treatment was not reached (NR; 95% CI, 9.0 years–NE; 95% CI, 108.6 months–NE). The 24-, 48-, and 60-month OS rates were all 100% (95% CI, 100%-100%).

The median OS after retreatment was 7.1 years (95% CI, 5.0-NE), which translated to 85.6 months (95% CI, 60.6-NE). The 24-, 48-, and 60-month OS rates were all 100% (95% CI, 100%-100%).

Although this analysis was not designed to evaluate safety, the study authors noted that previous findings from M13-365 have demonstrated that venetoclax plus rituximab is tolerable in this patient population.

“These findings support venetoclax-based retreatment as an option for patients with relapsed/refractory CLL who progress [following the completion of initial] venetoclax therapy,” study authors concluded.

References

1. Brander DM, Roberts AW, Kipps TJ, et al. Retreatment with venetoclax and rituximab combination following disease progression while off therapy in patients with chronic lymphocytic leukemia. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract P682.
2. Kater A, Harrup R, Kipps TJ, et al. Final 7-year follow up and retreatment substudy analysis of MURANO: venetoclax-rituximab (VenR)-treated patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL). Hemasphere. 2023;7(suppl):e492813f. doi:10.1097/01.HS9.0000967716.49281.3f