CLL Breakthrough: 100% Efficacy Reported for VenR Retreatment

Patients experiencing progression of their chronic lymphocytic leukemia (CLL) can safely and effectively be treated again with venetoclax and rituximab (VenR), a BCL2 inhibitor and an anti-CD20 antibody, respectively, with new results showing 100% of patients responded to this combination and had prolonged progression-free survival (PFS).¹ Overall, median PFS from first treatment with VenR was 9.5 years, and median PFS from retreatment was 4.9 years, according to the study findings published in HemaSphere.

Four male patients and 5 female patients were included in this analysis, the phase 1b M13-365 study (NCT01682616), with ages ranging from 58 years to 79 years; they were enrolled between August 6, 2012, and May 28, 2014. Total prior therapies ranged from 1 to 4; time on initial therapy, 139 to 1210 days; and time on retreatment, 130 to 2037 days. Prior to retreatment, their median lymphocyte count was 22.5 x 10⁹/L and maximum lymph node size was a median 34.8 mm. Three genomic features were measured, and of these, 1 patient each had del(17p) or a TP53 mutation and 2 patients exhibited IGHV-mutated disease. Best responses with initial therapy were complete response (CR; n = 6), CR with incomplete recovery (CRi; n = 2), and partial response (PR; n = 1). With retreatment, best responses comprised 3 CRs and 6 PRs. The study investigators conducted a longer-term analysis among the patients who achieved a CR or reached undetectable status via minimal residual disease (uMRD) measure.

Progressive disease after going off initial therapy was defined as 2 consecutive peripheral blood measures with MRD values greater than 10^–4 or a single measure greater than 10^–3. Prior to retreatment, disease status was confirmed through a CT scan or MRI and bone marrow biopsy. Retreatment protocol was a daily oral dose of 400 mg venetoclax, after a 5-week ramp-up; then 375 mg/m² rituximab started on day 1 of week 6 if needed and monthly doses of 500 mg/m² rituximab for 5 months.

Prior to initial therapy, 7 of these patients had uMRD status in their bone marrow alone (n = 1) or in both their bone marrow and peripheral blood (n = 6), 1 patient was MRD-positive in their bone marrow and peripheral blood, and 1 patient was MRD-positive in their bone marrow. Before initial retreatment, there was just 1 case of uMRD status in the bone marrow and peripheral blood; the remaining cases were uMRD status in the peripheral blood but MRD-positive in the bone marrow, 4 cases of MRD-positive status in the bone marrow and peripheral blood, and 3 cases of MRD-positive status in the peripheral blood.

Patients were off treatment for a median of 38.4 months (range, 17.3-68.7) prior to progressive disease and initiating retreatment; median time between confirmation of disease progression and retreatment was 4.9 months. After treatment restarted, the 9 patients achieved a PR or better, as previously stated, and as of the data cutoff of December 31, 2023, 4 have not progressed and have been off of therapy for more than 1 year.

A subanalysis conducted among 6 patients who acquired BCL2 mutations after previous venetoclax-based therapies showed no evidence of the mutation in 4 of the patients tested before treatment was reinitiated or in the remaining 2 tested after treatment was reinitiated. Further, of the patients tested for del(17p) or TP53 mutations before retreatment, all were negative for del(17p) but 1 patient was positive for TP53.

“As the protocol had the distinctive option, but not requirement, to discontinue treatment if in a deep response, it permitted the within‐trial comparison that demonstrated that PFS off therapy in deep response was like that of patients who remained on continuous therapy after achieving deep response,” the study authors wrote. “The M13‐365 study provided the first prospective evidence that CLL/SLL response can be maintained off treatment if patients achieved a deep response to initial VenR.”

Their results are both promising and strong because the median time off treatment that they saw was longer compared with other studies^2,3 and supports their theory that fixed-duration treatment could lessen patient risk of developing future treatment resistance.^4,5

References

1. Brander DM, Roberts AW, Kipps TJ, et al. Retreatment with venetoclax and rituximab following disease progression while off therapy in patients with chronic lymphocytic leukemia. Hemasphere. 2025;9(12):e70284. doi:10.1002/hem3.70284
2. Kater AP, Harrup R, Kipps TJ, et al. The MURANO study: final analysis and retreatment/crossover substudy results of VenR for patients with relapsed/refractory CLL. Blood. 2025;145(23):2733‐2745. doi:10.1182/blood.2024025525
3. Thompson MC, Harrup RA, Coombs CC, et al. Venetoclax retreatment of patients with chronic lymphocytic leukemia after a previous venetoclax‐based regimen. Blood Adv. 2022;6(15):4553‐4557. doi:10.1182/bloodadvances.2022007812
4. Popovic R, Dunbar F, Lu C, et al. Identification of recurrent genomic alterations in the apoptotic machinery in chronic lymphocytic leukemia patients treated with venetoclax monotherapy. Am J Hematol. 2022;97(2):e47‐e51. doi:10.1002/ajh.26411
5. Blombery P, Thompson ER, Nguyen T, et al. Multiple BCL2 mutations cooccurring with Gly101Val emerge in chronic lymphocytic leukemia progression on venetoclax. Blood. 2020;135(10):773‐777. doi:10.1182/blood.2019004205