Acalabrutinib-based chemo-free triplet shows high rates of MRD-negative CR in 1L MCL study
First-line (1L) acalabrutinib in combination with lenalidomide and rituximab (ALR) has demonstrated high rates of minimal residual disease (MRD)–negative complete remission (CR) in patients with mantle cell lymphoma (MCL), including patients with TP53 mutations, in a single-arm phase II trial reported at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition.
The results also suggest that real-time MRD analysis can facilitate response-adapted treatment de-escalation during the maintenance phase of therapy to minimize toxicity, which warrants further evaluation. [Ruan J, et al, ASH 2022, abstract 73]
The study included 24 patients (median age, 64 years; male:female ratio, 3.8:1) with treatment-naïve stage III/IV MCL. Of these patients, 96 percent had bone marrow involvement, and 29 percent had TP53 mutations. Mantle Cell Lymphoma International Prognostic Index (MIPI) scores were of low-risk category in 37 percent of patients, intermediate-risk category in 42 percent of patients, and high-risk category in 21 percent of patients. Ki67 index was <30 percent in 63 percent of patients, and 21 percent of patients had elevated lactate dehydrogenase (LDH) levels.
Treatment provided in the study included induction and maintenance, with the induction phase comprising the first 12 cycles of treatment and the maintenance phase starting from cycle 13 until disease progression or treatment discontinuation. Acalabrutinib was administered at 100 mg BID continuously during both phases. Lenalidomide was administered at 15 mg daily on days 1–21 of 28-day cycles for 12 cycles during induction, with dose escalation to 20 mg if tolerated, followed by dose reduction to 15 mg during the maintenance phase. Rituximab was administered weekly for 4 weeks during cycle 1, followed by once every other cycle throughout induction and maintenance.
As of July 2022, after a median follow-up of 19 months, all 24 patients (100 percent) remained on study without evidence of disease progression. Twenty-one patients had completed 12 cycles of induction therapy and 11 patients had completed 24 cycles of treatment.
Among 21 patients evaluable for the primary endpoint of MRD-negative (<10-6) CR rate at the conclusion of induction therapy, objective response rate was 100 percent, and CR rate was 90.5 percent after 12 cycles of treatment. MRD negativity (<10-6) in peripheral blood was achieved in 50 percent of patients (n=12/24) after six cycles, 71 percent of patients (n=15/21) after 12 cycles, and 82 percent of patients (n=9/11) after 24 cycles. Among patients with TP53 mutations, 80 percent (n=4/5) achieved MRD negative (<10-6) CR after 12 treatment cycles.
In patients who achieved MRD-negative CR, acalabrutinib and lenalidomide could be discontinued after 24 cycles. Seven patients in MRD-negative CR had discontinued acalabrutinib and lenalidomide.
“Patients continued rituximab treatment as tolerated, because previous research suggests that rituximab is associated with improved survival outcomes and durability of MRD response,” explained Dr Jia Ruan of Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterrian Hospital in New York, US, who presented the results at ASH 2022. “The majority of patients were on rituximab maintenance for as long as they were on the study, with the longest being more than 3 years as of early December 2022.”
In the study, the ALR triplet regimen was well tolerated, with expected adverse events. The most common grade 3/4 haematologic and nonhaematologic toxicities were asymptomatic neutropenia (38 percent) and rash (42 percent), respectively. Other grade 3/4 toxicities included thrombocytopenia, anaemia, fatigue, nausea, vomiting, and hyponatraemia (4 percent each).
Four incidences of secondary malignancy were reported, including one renal cell carcinoma requiring removal, and three nonmelanomatous skin cancer.
“As this was a single-arm phase II study, the data should be viewed as exploratory,” said Ruan. “An expansion cohort of acalabrutinib in combination with lenalidomide and obinutuzumab is being launched.” [NCT03863184]