Acalabrutinib Regimen Demonstrates Efficacy in De Novo Mantle Cell Lymphoma

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The combination of acalabrutinib (Calquence), umbralisib (Ukoniq), and ublituximab-xxiy (Briumvi; AU2) elicited high response and undetectable minimal residual disease (uMRD) rates in patients with de novo mantle cell lymphoma (MCL), according to updated data from a phase 2 study (NCT04783415) presented during the 2024 ASH Annual Meeting.¹

In evaluable patients (n = 12), AU2 elicited an objective response rate (ORR) of 100%, all of which were complete responses (CRs). At a median follow-up of 29 months, the 2-year progression-free survival (PFS) rate was 63% and 2-year overall survival (OS) rate was 88%. In the subset of patients with TP53-mutated disease (n = 6), the respective PFS and OS rates at 2 years were 21% and 67%.

Among those with available data (n = 11), 73% achieved uMRD. A total of 3 patients did not have documented uMRD, 1 patient experienced disease progression at cycle 6, 1 patient was lost to follow-up while in CR, and 2 patients lost their MRD response.

“AU2 was a highly effective regimen in unfit patients, and responses to subsequent lines were not impaired,” Paolo Lopedote, MD, a fellow in Hematology and Medical Oncology at the City of Hope National Medical Center in Duarte, California, said in a poster presentation of the data. “This shows that chemotherapy-free approaches are feasible in the frontline setting, and patients with TP53 mutations continued to have worse outcomes.”

Patients with MCL are often elderly and have comorbid conditions, which make them not eligible to receive intensive chemotherapy. Moreover, those with tumors harboring TP53 mutations are known to have disease that is resistant to chemotherapy. As such, chemotherapy-free regimens are needed for these patients with high-risk features, according to Lopedote. The CD20 monoclonal antibody ublituximab and the PI3Kδ/casein kinase-1ε inhibitor umbralisib have both shown activity when used as single agents and in combination in patients with relapsed/refractory non-Hodgkin lymphoma.

“The combination of acalabrutinib with U2 had the potential of further synergy through multistep BCR pathway targeting,” Lopedote noted.

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 a twice-daily dose of 100 mg, umbralisib at a daily dose of 800 mg on days 1 to 14 of cycle 1 and days 1 to 7 of subsequent cycles, and ublituximab at 900 mg on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles. Each cycle was comprised of 28 days. After 6 cycles, patients received maintenance treatment with oral agents and ublituximab every 2 cycles; this was planned for 24 cycles.

The primary objective of the study was CR rate by Lugano criteria, and secondary objectives included uMRD rate at 10^-6 sensitivity, OS and PFS, duration of response, and safety by CTCAE version 5.0. MRD was evaluated prior to treatment, followed by cycles 1, 2, 8, and 14, and then again at the end of treatment.

“The study was suspended in 2022 by the FDA and U2 manufacturing in oncology was discontinued,” Lopedote said.

Previous data from the trial were shared during the 2022 ASH Annual Meeting.² Twelve patients were included in the updated analysis.¹ The median patient age was 71 years (range, 55-79), all were White, and 75% were male. Moreover, 50% of patients had TP53 abnormalities and 1 had CK. Of 11 patients with available Mantle Cell Lymphoma International Prognostic Index information, 55% had high-intermediate or worse disease. Of those with available Ki-67 information (n = 10), 40% had a Ki-67 of at least 30%.

Of the 12 patients, 3 patients were still receiving acalabrutinib at the time of the data cutoff. Nine patients terminated treatment due to progressive disease (n = 3), toxicity (n = 1), COVID-19 (n = 2), XRT for prostate cancer (n = 1), and discontinued manufacturing of U2 (n = 2).

Four of the 12 patients experienced disease progression—3 while on therapy and 1 after completion of U2. Two patients died on the study. Of the 4 who experienced disease progression, 3 responded to subsequent lines of treatment and 1 progressed to multiple lines and died from progressive disease.

The most common all-grade adverse effects (AEs) reported with the regimen included infusion-related reaction (IRR; 75%), increased AST (67%), diarrhea (58%), headache (58%), decreased platelet count (50%), decreased white blood cell count (50%), hypertension (42%), anemia (42%), decreased lymphocyte count (42%), nausea (33%), increased ALT (33%), decreased neutrophil count (33%), bruising (33%), vomiting (25%), weight loss (25%), maculopapular rash (25%), fatigue (17%), increased alkaline phosphatase (17%), hyperglycemia (17%), sinus tachycardia (17%), increased blood lactate dehydrogenase (17%), cough (17%), and pruritus (17%).

The most common grade 3 or 4 AEs reported with the combination were increased ALT (33%), increased AST (33%), IRR (33%), decreased lymphocyte count (25%), decreased neutrophil count (17%), supraventricular tachycardia (8%), diarrhea (8%), decreased platelet count (8%), increased blood bilirubin (8%), decreased white blood cell count (8%), hyperuricemia (8%), COVID-19 (8%), atrial fibrillation (8%), lung infection (8%), increased alkaline phosphatase (8%), meningitis (8%), and tumor lysis syndrome (8%).

Study limitations included that it was prematurely closed, had a small number of patients, and had limited MRD data, Lopedote concluded.

Disclosures: Lopedote did not cite any relevant conflicts of interest.

References

1. Lopedote P, Shouse G, Muir A, et al. Acalabrutinib, umbralisib and ublituximab regimen (AU2) demonstrates high response rate and undetectable molecular minimal residual disease (MRD) in patienets (pts) with de novo mantle cell lymphoma (MCL). Blood. 2024;144(suppl 1):1633. doi:10.1182/blood-2024-200963
2. Danilov AV, Muir A, Melgar I, et al. A phase II trial of acalabrutinib in combination with PI3Kδ inhibitor umbralisib and the anti-CD20 antibody ublituximab (AU2) in patients with previously untreated mantle cell lymphoma (MCL). Blood. 2022;140(suppl 1):3633-3634. doi:10.1182/blood-2022-159805