Venetoclax Plus R2 Is Safe and Effective in Frontline MCL

Tycel Jovelle Phillips, MD

The triplet regimen of rituximab (Rituxan), venetoclax (Venclexta), and lenalidomide (Revlimid) was shown to be a safe frontline regimen in patients with mantle cell lymphoma (MCL) and showed early signs of efficacy.

“Early preliminary data [indicate] that the regimen was effective in patients with several high-risk features…as indicated by complete remission [CR] rate and negative MRD [minimal residual disease] testing,” Tycel Jovelle Phillips, MD, clinical associate professor in the Department of Medicine at University of Michigan Health Rogel Cancer Center in Ann Arbor, Michigan, said in a presentation during the 2021 International Conference on Malignant Lymphoma.

Rituximab plus lenalidomide (R2) has previously demonstrated efficacy in MCL treatment, and venetoclax, has demonstrated preclinical synergy with lenalidomide. The investigators believed that the triplet regimen would be safe and would improve objective response rate, time to best response, and potentially induce MRD negativity vs R2 alone.

The trial enrolled patients with untreated MCL who required treatment. They were treated with lenalidomide 20 mg daily on days 1 through 21 every 28 days plus venetoclax starting at 50 mg and escalating weekly up to 400 mg daily and rituximab 375 mg/m² on days 1, 8, 15, and 22 of cycle 1 as induction therapy for 12 planned cycles that was later amended to 6 cycles. Patients were then assessed by positron emission tomography (PET)/CT scan and with MRD testing every 3 cycles during induction and yearly during maintenance. Those who achieved a CR and MRD negativity who were ineligible for transplant went on to maintenance therapy with lenalidomide 10 mg daily on days 1 through 21 every 28 days plus venetoclax 400 mg daily and rituximab 375 mg/m² only on even cycles. With maintenance therapy, venetoclax was given for 12 months, lenalidomide for 24 months, and rituximab for 36 months.

Immunoglobulin next-generating sequencing was used to identify and quantify disease- associated sequence rearrangements to 10-6 in peripheral blood samples.

A total of 30 patients were enrolled, 28 were treated, and 82% remained on treatment at data cutoff.

Of the 28 treated patients, 64% were male, all were Caucasian and had stage III or IV disease, 79% had an ECOG performance status of 0 or 1, 93% had bone marrow involvement, and 88% had high-risk disease. Patients had a median age of 65 years (range, 46-72). Additionally, 14% had blastoid disease, 7% had pleomorphic disease, 18% had mutated TP53 status, and 29% had abnormal cytogenetics.

All patients underwent PET/CT scan at 3 months, and 67% of these patients showed a CR, 29% had a partial response (PR), and 3% had progressive disease (PD). At 6 months, 27 patients were scanned, and 78% had a CR, 19% had a PR, and 3% had PD. Sixteen patients were scanned at 9 months, and 94% had a CR while the remainder had PD. At 12 months, all 12 patients who underwent PET/CT had a CR.

The duration of clinical response ranged from 2.8+ months to 24.4+ months as of data cutoff. Five patients are no longer on the trial, 3 due to disease progression and 2 for other reasons. All patients who progressed had TP53 mutations.

The majority of patients who had positive MRD at the first assessment changed to MRD negative in subsequent assessments. Concordance was seen in most patients and assessments between flow cytometry and next-generation sequencing.

Progression-free survival rates were 96.4% (95% CI, 89.8%-100%) at 3 months, 92.0% (95% CI, 82.0%-100%) at 6 months, 92.0% (95% CI, 82.0%-100%) at 9 months, and 85.5% (95% CI, 71.0%-100%) at 12 months

The median duration of treatment was 308 days (range, 237-636). Dose reductions or delays were reported in 53% of patients, and dose discontinuations due to adverse events (AEs) were reported in 21%.

The period for dose-limiting toxicities (DLTs) was 42 days from the initiation of venetoclax. All patients were safely able to escalate venetoclax up to the 400-mg daily dose, and no DLTs were reported.

The most common AEs of any grade were neutrophil count decrease (89%), platelet count decrease (72%), diarrhea (41%), anemia (36%), fatigue (25%), lymphocyte count decrease (25%), dyspnea (23%), and white blood cell decrease (21%).

There were several grade 3 or higher AEs, the most common of which were neutrophil count increase (62%), platelet count decrease (50%), and diarrhea (14%). Two secondary cancers were reported on the study— 1 adenocarcinoma of unknown primary and 1 cutaneous squamous cell carcinoma—and 4 deaths were reported on the study, 2 from lymphoma and 2 from other causes.

Phillips noted that the investigators plan to expand the study with 50 patients without a TP53 mutation. They are also looking to modify the regimen to target patients with high-risk features, including TP53 mutations.

_REFERENCE:

_{Phillips TJ, Danilov A, Bond DA, et al. The combination of venetoclax, lenalidomide and rituximab in patients with newly diagnosed mantle cell lymphoma induces high response rates and MRD undetectability. Presented at: 16th International Conference on Malignant Lymphoma; June 19-22, 2021; virtual. Abstract 061.}