Acalabrutinib, umbralisib, and ublituximab (AU2) have shown promising efficacy in patients with previously untreated mantle cell lymphoma (MCL), according to data from a phase 2 study presented at the 2024 ASH Annual Meeting. The regimen achieved a 100% objective response rate (ORR) with complete responses (CRs) in all evaluable patients (n = 12).
High Response and MRD Negativity
The study (NCT04783415) revealed that at a median follow-up of 29 months, the 2-year progression-free survival (PFS) rate was 63%, and the 2-year overall survival (OS) rate was 88%. Among patients with available data (n = 11), 73% achieved undetectable minimal residual disease (uMRD). However, outcomes were less favorable in the subset of patients with TP53-mutated disease (n = 6), with 2-year PFS and OS rates of 21% and 67%, respectively.
Chemotherapy-Free Approach
Paolo Lopedote, MD, from City of Hope National Medical Center, highlighted the potential of this chemotherapy-free approach, stating, "AU2 was a highly effective regimen in unfit patients, and responses to subsequent lines were not impaired... This shows that chemotherapy-free approaches are feasible in the frontline setting, and patients with TP53 mutations continued to have worse outcomes."
Study Design and Dosing
The open-label, single-center, investigator-initiated, phase 2 study enrolled patients with de novo MCL who were at least 65 years of age, at least 50 years of age and not willing to undergo intensive chemoimmunotherapy, or at least 18 years of age with tumors harboring TP53 mutations or complex karyotype. Patients received acalabrutinib at 100 mg twice daily, umbralisib at 800 mg daily (days 1-14 of cycle 1, days 1-7 of subsequent cycles), and ublituximab at 900 mg (days 1, 8, and 15 of cycle 1, day 1 of subsequent cycles). Each cycle was 28 days. After 6 cycles, patients received maintenance treatment with oral agents and ublituximab every 2 cycles, planned for 24 cycles.
The primary objective was CR rate by Lugano criteria. Secondary objectives included uMRD rate at 10-6 sensitivity, OS and PFS, duration of response, and safety. MRD was evaluated prior to treatment and during cycles 1, 2, 8, and 14, and at the end of treatment.
Adverse Events and Limitations
The most common all-grade adverse effects (AEs) included infusion-related reaction (IRR; 75%), increased AST (67%), diarrhea (58%), and headache (58%). Grade 3 or 4 AEs included increased ALT (33%), increased AST (33%), and IRR (33%). The study was limited by its premature closure, small sample size, and limited MRD data, according to Lopedote.
Context
Mantle cell lymphoma (MCL) often affects elderly patients with comorbidities, making them ineligible for intensive chemotherapy. Tumors with TP53 mutations are also known to be resistant to chemotherapy. The combination of acalabrutinib with umbralisib and ublituximab targets the B-cell receptor (BCR) pathway, potentially offering synergistic effects. However, the study was suspended in 2022 by the FDA, and U2 manufacturing in oncology was discontinued.
