Acalabrutinib, umbralisib and ublituximab regimen (AU2) demonstrates high response rate and undetectable molecular minimal residual disease (MRD) in patients (pts) with de novo mantle cell lymphoma (MCL)

We present an update of a phase 2 study of AU2 in pts with previously untreated MCL (NCT04783415).

This open-label phase 2 investigator-sponsored study enrolled pts with de novo MCL, aged ≥65 years, unwilling to undergo intensive induction, and/or with TP53 aberrations/complex karyotype. Acalabrutinib was given at 100 mg PO twice daily, umbralisib 800 mg PO daily (amended to days 1-14 of cycle 1 and days 1-7 of subsequent cycles) starting with cycle 1 day 1; ublituximab 900 mg intravenously on days 1, 8, 15 of cycle 1 and day 1 of subsequent cycles. Each cycle was 28 days. After 6 cycles, pts continued maintenance with oral agents and ublituximab every 2 cycles (planned for 24 cycles). The primary objective was efficacy by Lugano criteria; secondary objective was safety. MRD was assessed via clonoSEQ assay (Adaptive Biotech). Undetectable MRD (uMRD) was defined as 10-6. The study was suspended by the FDA in 02/2022 due to safety concerns with PI3K inhibitors.

Twelve pts were enrolled. Median age was 70 years (range 55-79), 9/12 (75%) were male; 6/12 pts had a TP53 mutation, 1 had complex karyotype. Due to recurrent AST/ALT abnormalities to acalabrutinib, four pts continued on U2 alone.

All 12 pts achieved a complete response. Eleven pts had MRD data available, and eight (73%) achieved uMRD.

Three pts remain on therapy. Four pts progressed and three achieved an ongoing response to subsequent therapies. Two pts died: one a month from COVID-19; one due to PD. 2-year PFS and OS are 63% and 88% respectively (21% and 67%, respectively among pts with TP53 mutation).

Most common grade ≥3 toxicities were AST increase, ALT increase, and IRRs (33% each).

AU2 is a highly effective regimen in pts with previously untreated MCL, and achieves a high molecular uMRD rate.