MRD-Driven Venetoclax, Lenalidomide, and Rituximab Combo Demonstrates Efficacy Among Patients With R/R Mantle Cell Lymphoma

According to results from a phase 1b/2 study, minimal residual disease (MRD)-driven venetoclax, lenalidomide, and rituximab treatment is feasible, tolerable, and demonstrates efficacy among patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL), including after Bruton’s tyrosine kinase (BTK) inhibitor failure. 

Eligible patients included 59 participants of a median age of 72 years with R/R MCL. Patients were enrolled in this open-label, single arm, multicenter, Nordic Lymphoma Group trial at 14 centers in Sweden, Finland, Norway, and Denmark. The primary end point was overall response rate (ORR) measured at 6 months, and secondary end points included ORR in patients previously treated with a Bruton’s tyrosine kinase inhibitor (BTKi), ORR in patients with a TP53 mutation, complete response (CR) rate, safety, molecular remission rate, progression-free survival (PFS), and overall survival (OS).

In the phase 1b portion of the study, patients received rituximab once weekly for 4 weeks during cycle 1, then every 8 weeks. The initial dose was given intravenously at a dose of 375 mg/m². Future doses could then either be given intravenously at the same dose, or as a subcutaneous injection of 1400 mg. No dose reductions were permitted for rituximab. Lenalidomide was given orally on days 1 to 21 in each cycle of 28 days. Venetoclax was given orally daily, and the dose was ramped up, 20 mg, 50 mg, 100 mg, 200 mg, for 1 week each, until the target dose was reached. It was noted that for both venetoclax and lenalidomide, the phase 1b part of the trial followed a sequential dose escalation “3 + 3” design.

Following dose escalation, the recommended phase 2 dose was lenalidomide 20 mg daily, days 1 to 21; venetoclax 600 mg daily after ramp-up; and rituximab 375 mg/m² weekly for 4 weeks, then every 8 weeks. Additionally, MRD monitoring by real-time quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) was performed every 3 months. When MRD-negativity in the blood was reached, treatment was continued for another 3 months; however, if MRD-negativity was then confirmed, treatment stopped.

Results demonstrated that at 6 months, the ORR was 63% (29 complete remission [CR], 8 partial remission [PR]), and 40% (4 CR, 2 PR) for patients previously failing a BTKi. The median PFS was 21 months, and the median OS measured at 31 months. A TP53 mutation was associated with inferior PFS (P < .01). Overall, 28 patients (48%) discontinued treatment in molecular remission, and 25 remained MRD negative after a median of 17.4 months. 

Notable adverse events included frequent hematological toxicity, with 52 of 59 (88%) patients with grade 3 to 4 neutropenia and 21 of 59 (36%) patients with grade 3 to 4 thrombocytopenia. In total, 28 patients (47%) died while on the study.

Mats Jerkeman, MD, PhD, Lund University and Skane University Hospital, Lund, Sweden, and colleagues concluded, “MRD-driven venetoclax [lenalidomide and rituximab] is feasible and tolerable and shows efficacy in R/R MCL, also after BTK inhibitor failure.”

“In this trial, 98% were evaluable by MRD, and we were able to show that discontinuing treatment after a minimum treatment duration of 6 months was feasible in 48% of the patient population,” they added, “However, although we could show that an MRD-guided approach is feasible, it remains to be proven to be superior in terms of sensitivity compared with the use of clinical assessment only.”

The authors also noted that treatment regimens for R/R MCL have rapidly evolved since the initiation of this trial, commenting that “At that point, BTK [inhibitor]s were not generally approved for this indication in the Nordic area, but will likely soon be part of standard first-line treatment.”

Source:

Jerkeman M, Kolstad A, Hutchings M, et al. MRD-driven treatment with venetoclax-R2 in mantle cell lymphoma: The Nordic Lymphoma Group MCL7 VALERIA trial. Blood Adv. (2024) 8 (2): 407–415. 10.1182/bloodadvances.2023011920