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)

Background. Frontline treatment of MCL is evolving with the role of autologous stem cell transplant increasingly under question in the era of novel agents. Bruton tyrosine kinase inhibitors have shown efficacy in relapsed MCL as well as de novo MCL when combined with chemo-immunotherapy and other novel agents. Here we present an update of a phase 2 study of AU2 in pts with previously untreated MCL (NCT04783415).

Methods. This open-label phase 2 investigator-sponsored study enrolled pts with de novo MCL, aged ≥65 years, those unwilling to undergo intensive induction, and/or pts with high-risk genetics (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 study objective was efficacy (complete response [CR]) by Lugano criteria; secondary objective was safety. MRD was assessed in the peripheral blood via clonoSEQ assay (Adaptive Biotech). Undetectable MRD (uMRD) was defined as 10^-6. Fisher’s exact test was used to assess the association between uMRD and subsequent disease progression (PD). The study was suspended by the FDA in 02/2022 due to safety concerns with PI3K inhibitors.

Results. Twelve pts were enrolled. Median age was 70 years (range 55-79), 9/12 (75%) were male; all had an ECOG performance status 0-1; 6/12 pts had a TP53 mutation and 1 additional pt had complex karyotype. MIPI-c score was available on 11/12 (Ki-67 on 10/12 pts): 6/11 (55%) had at least high-intermediate risk, and 4/10 a Ki-67 ≥30%. The first two pts enrolled in the study developed grade 3-4 AST/ALT elevation by mid-cycle 2. As a result, the trial was amended to administer umbralisib on days 1-14 of cycle 1 and days 1-7 of subsequent cycles. In total, 4 pts were unable to tolerate acalabrutinib due to recurrent AST/ALT abnormalities and continued on U2 therapy alone. The remaining 8 pts tolerated all three drugs. All 12 pts achieved CR (overall response rate 100%, CR rate 100%).

Eleven pts had MRD data available (baseline assay failed in 1 pt). Eight pts (73%) achieved uMRD, 6 at cycle 8, 1 by cycle 26, and 1 at the end of therapy. Three pts did not have a documented uMRD: one had a PD, one was lost to follow-up while in CR, and one achieved a CR (still ongoing) without receiving further therapy. Of 8 pts who had uMRD, three became MRD-detectable before experiencing PD. Loss of uMRD or failure to achieve uMRD was associated with PD (p=0.048) and was common among pts with TP53 mutation.

At this time, 3/12 pts remain on therapy having received a range of 34-38 months of therapy thus far (one of them with TP53 mutation); the other 9 pts terminated after a median of 21 (range 5-29) months: 3 due to PD, 1 due to adverse event, 2 due to COVID, 1 due to need for XRT for prostate cancer, and 2 due to discontinued manufacturing of U2.

Four pts progressed: 3 while on therapy and one - 7 months after completing U2 therapy. Two pts died. One of them terminated treatment due to COVID-19 and died within a month; the other terminated treatment due to PD and died 18 months later. The 10 survivors had a median follow-up of 29 (range 9-38) months. 2-year PFS and OS are 63% and 88% respectively. Among pts with TP53 mutation, 2-year PFS and OS were 21% and 67%, respectively.

Most common all-grade toxicities were infusion-related reactions (IRR; 75%), AST increased (67%), diarrhea, and headache (58%). Most common grade ≥3 toxicities were AST increase, ALT increase, and IRRs (33% each).

Of 12 pts, 4 received subsequent therapies after stopping AU2. Two pts were switched to zanubrutinib due to PD on U2, both achieved response. One patient achieved CR with CAR-T cell therapy. One pt died after failing multiple lines of therapy (including CAR-T). Of the 5 pts who did not receive further therapy, 1 died soon after therapy discontinuation due to COVID-19, 1 was lost to follow-up due to progressive dementia, and the other 3 remained in remission without additional therapy.

Conclusion. AU2 is a highly effective regimen in pts with previously untreated MCL, including those with high-risk genetics (100% CR rate), and achieves a high molecular uMRD rate. Pts who develop progressive disease can be effectively salvaged with subsequent therapies.