Zanubrutinib/Rituximab Induction May Be Safe and Effective in Newly Diagnosed Mantle Cell Lymphoma

Adding the second-generation BTK inhibitor zanubrutinib (Brukinsa) to up-front induction with rituximab (Rituxan) with or without autologous stem cell transplant (ASCT) as consolidation showed early efficacy and tolerability in treatment-naive patients with newly diagnosed mantle cell lymphoma (MCL), according to data from a prospective phase 2 trial (NCT05504603) presented during the 2024 EHA Congress.¹

Among the 29 patients who completed at least 3 cycles of zanubrutinib plus rituximab induction, 24 achieved a complete response (CR), 3 experienced a partial response (PR), 1 patient had stable disease, and 1 patient experienced disease progression. The latter 2 patients were subsequently taken off the trial.

Moreover, the overall response rate (ORR) after 3 cycles of treatment was 93.1%, comprising a CR rate of 82.7%. Of the 25 patients who completed the planned 5-cycle treatment, all achieved a CR. Moreover, 68.0% of these patients achieved minimal residual disease negativity. Five of these patients continued on to receive ASCT.

At a median follow-up of 13.6 months, the 2-year overall survival (OS) and progression-free survival (PFS) rates were 100% and 96.6%, respectively; the median OS and PFS were undefined.

Regarding safety, toxicities observed during the whole treatment course included transient alanine aminotransaminase elevation (n = 7), oral mucositis (n = 6), hematological toxicities (n = 5), pyrexia (n = 5), infusion-related response (n = 2), and COVID-19–related pneumonia (n = 5). All adverse effects (Aes) were transient and reversible, and no atrial fibrillation and bleeding events were reported.

“This study demonstrates a favorable efficacy and tolerable safety of [this] chemotherapy-free regimen in [patients with] newly diagnosed MCL and [could] expand therapeutic options for newly diagnosed MCL,” lead study author Changju Qu, MD, PhD and colleagues at the First Affiliated Hospital of Soochow University, Suzhou, China, wrote in a poster presentation of the data.

Frontline treatment strategies in MCL typically involve intensive chemoimmunotherapy induction with or without consolidation ASCT; however, this approach is associated with an increase in both short- and long-term toxicities.

In the single-arm phase 2 Window-1 study (NCT02427620), up-front induction with ibrutinib (Imbruvica) plus rituximab was found to minimize chemotherapy exposure for previously untreated patients with MCL, thereby reducing AEs. Additionally, the ORR was 98% (95% CI, 95%-100%) in patients (n = 131) treated in part A of the study, who received 12 cycles of the frontline regimen. These results showed that bringing next-generation BTKs inhibitors into the frontline setting was feasible and effective in MCL.2

Given the response rates and safety demonstrated by zanubrutinib in patients with relapsed/refractory MCL, investigators accordingly hypothesized that combining zanubrutinib with rituximab may eliminate the need for chemotherapy in the up-front management of newly diagnosed disease.1

Study Overview

This prospective, open-label, phase 2 study enrolled patients 18 years of age or older with locally histopathologically confirmed newly diagnosed MCL without prior treatment exposure. An ECOG performance status of 2 or less was also required.

Upon enrollment, patients received 160 mg of oral zanubrutinib twice daily alongside 375 mg/m2 of rituximab administered weekly for cycle 1 and then every 4 weeks on day 1 of cycles 2 to 5. Patients who achieved CR or PR subsequently received either zanubrutinib maintenance if older than 70 years of age and/or were unfit, or ASCT if they were younger than 70 years of age and fit. Treatment continued until intolerable toxicity or disease progression.

The study’s primary end points were ORR and CR after the completion of cycle 3, cycle 5, and ASCT. Key secondary end points included 2-year OS, 2-year PFS, and safety.

A total of 33 patients were enrolled onto the study. The median age in the overall population was 61 years (range, 43-77). The majority of patients were male (81.8%), had stage III/IV disease (81.8%), and had classic morphology (84.8%). Regarding international prognostic index score, 48.5%, 24.2%, 21.2% and 6.1% of patients had low-medium–risk, low-risk, high-medium–risk, and high-risk disease, respectively. Of the twenty-one patients who underwent next-generation sequencing to identify key genetic mutations, 9 (42.9%) harbored ATM mutations and 3 (14.3%) had TP53 mutations.

References

1. Qu C, Ping N, Zou R, et al. Zr Study: A prospective phase II study of zanubrutinib-rituximab chemo-Free therapy with or without autologous stem cell transplantation in newly diagnosed mantle cell lymphoma. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract P1120.
2. Wang ML, Jain P, Zhao S, et al. Ibrutinib-rituximab followed by R-HCVAD as frontline treatment for young patients (≤65 years) with mantle cell lymphoma (WINDOW-1): a single-arm, phase 2 trial. Lancet Oncol. 2022;23(3):406-415. doi:10.1016/S1470-2045(21)00638-0