Acalabrutinib May Be an Effective Addition to Lenalidomide/Rituximab Regimen in Frontline MCL

Triplet therapy with the BTK inhibitor acalabrutinib (Calquence) plus lenalidomide (Revlimid) and rituximab (Rituxan) appeared to yield high rates of complete response (CR) in the frontline treatment of patients with mantle cell lymphoma (MCL), according to findings from a single-arm phase 2 study (NCT03863184).

As of July 2022, all patients who underwent induction therapy (n = 24) have completed treatment and moved on to the maintenance setting after a median follow-up of 23 months. Twelve have exceeded 24 months of treatment, of whom 9 have had de-escalated treatment and 2 discontinued due to lymphoma progression. The overall response rate in the intent-to-treat population was 100% (90% CI, 87%-100%) among 21 patients evaluable, and the CR rate was 83% after 12 cycles of treatment.

“The initial treatment of mantle cell lymphoma continues to evolve with the introduction of targeted agents,” lead study author Jia Ruan, MD, PhD, professor of clinical medicine in the Division of Hematology and Medical Oncology at Weill Cornell Medicine in New York, New York. “The triple biologic combination of acalabrutinib, lenalidomide, and rituximab is well tolerated [and] produces high rates of complete and molecular remission.”

The median age at study entry was 64 years (range, 35-77) and most patients enrolled were men (79%). Most (96%) had bone marrow involvement and a Ki67 index lower than 30%(63%). All patients had an ECOG performance status of 0 or 1 and stage III or IV disease. TP53 mutations presented in 29% of patients.

The study assessed the triplet therapy in both the induction (cycles 1-12) and maintenance (cycle 13) settings. Patients received oral acalabrutinib at 100 mg per day throughout both phases. They also received lenalidomide at 15 mg daily on days 1 to 21 of each 28-day cycle for a total of 12 cycles during induction. This dose could be escalated to 20 mg if tolerated and was reduced to 15 mg during maintenance. Patients also received intravenous rituximab every week during cycle 1 and then once every other cycle during the remaining induction and maintenance cycles. Investigators used AdaptiveBiotech ClonoSeq assay to measure peripheral blood MRD.

At a median follow-up of 23 months, the 2-year progression-free survival (PFS) rate was 86.7% (95% CI, 69.5%-100%) and the 2-year overall survival (OS) rate was 100%.

“We’re more comfortable thinking about 2 years [of treatment] in selected patients, like those without high-risk disease features,” Ruan said. “Any [duration] shorter than that requires additional study.”

Peripheral blood minimal residual disease (MRD) was undetectable at 1x10^-6 sensitivity in 50% patients after 6 treatment cycles, a rate which increased to 71% after 12 cycles and then 82% after 24 cycles. All but one patient with TP53-mutant disease (80%) achieved an MRD-negative CR after 12 cycles.

“Real-time MRD analysis facilitates response-adapted treatment deescalation during maintenance to minimize toxicity, which warrants further evaluation in future studies,” Ruan said.

The most prevalent grade 3/4 hematologic toxicities included asymptomatic neutropenia (38%), thrombocytopenia (4%), and anemia (4%) in the induction setting and neutropenia (5%) and anemia (5%) in the maintenance setting. Moreover, the most frequent high-grade non-hematologic adverse effects were rash (42%) and fatigue (4%) in the induction setting and fever (10%), nausea (5%), and abdominal pain (5%) in the maintenance setting.

Grade 3/4 COVID-19 (13%), pneumonia (8%), Zoster reactivation, and urinary tract infection (4%) were the most common infections that occurred in the induction setting, along with pneumonia (14%) and COVID-19 (14%) in the maintenance setting.

When asked about toxicity management, Ruan said, “The cutaneous reactions were rather more disturbing to our patients because they could see them, so those were very promptly managed by dose adjustment, systemic steroid use, or some break [in treatment]. However, those generally don’t recur. As for neutropenia, which seems to be ongoing, we rely strictly on our protocol to dose-adjust.”

Acalabrutinib and lenalidomide will be further examined in combination with obinutuzumab (Gazyva) in a planned expansion cohort.

These data were presented at the 2022 American Society of Hematology (ASH) Annual Meeting.

Reference

Ruan J, Leonard JP, Chen GZ, et al. Phase 2 trial of acalabrutinib-lenalidomide-rituximab (ALR) with real-time monitoring of MRD in patients with treatment-naïve mantle cell lymphoma. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, Louisiana. Abstract 73.