A phase II study of acalabrutinib in combination with R-CHOP for previously untreated transplant-ineligible mantle cell lymphoma patients in Spain (the SOUND-MCL Study)

Abstract Background and Significance Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy for which more effective therapeutic approaches are needed, particularly in patients who are ineligible for intensive regimens. Covalent Bruton tyrosine kinase inhibitors (BTKi), when added to first-line therapy with bendamustine-rituximab (BR), have demonstrated to add significant benefit in progression-free survival (PFS) in this setting. Recent data from the ECHO study led to regulatory approval of acalabrutinib plus BR. However, in Spain, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) remains widely used as initial treatment for transplant-ineligible patients. While the combination of acalabrutinib and R-CHOP has been tested in patients eligible for stem cell transplantation, there is a lack of prospective evidence regarding its use in patients ineligible for intensive treatment. This unmet need provides the rationale for evaluating acalabrutinib plus R-CHOP in the first-line treatment of newly diagnosed MCL patients not eligible for autologous stem cell transplantation. Study Design and Methods SOUND-MCL (EU CT Number 2025-521152-34-00; ClinicalTrials.gov Number NCT07029737) is a multicenter, open-label, single-arm phase II study that plans to enroll 55 patients with newly diagnosed, transplant-ineligible MCL from approximately 20 sites in Spain. Main eligibility criteria include age ≥18 years, histologically confirmed MCL previously untreated and unsuitable for autologous stem cell transplant, radiologically measurable lymphadenopathy, splenomegaly and/or extranodal lymphoid malignancy, and Eastern Cooperative Oncology Group (ECOG) performance status ≤2. Patients will receive acalabrutinib (100 mg twice daily) from Day 1 (D1) along with six 21-day cycles of R-CHOP as induction, followed by 24 months of rituximab maintenance (1 dose every 8 weeks, up to 12 doses) in those patients achieving complete or partial response (CR, PR) after induction. In patients achieving less than PR, maintenance with single agent acalabrutinib will be allowed if a clinical benefit can be demonstrated. Treatment with acalabrutinib at 100 mg twice daily will continue until disease progression or unacceptable toxicity. A safety run-in will be performed for the first 6 patients older than 75 years after the completion of 3 cycles of acalabrutinib + R-CHOP. A confirmatory assessment of sufficient efficacy for the acalabrutinib + R-CHOP combination will also be performed after the first 10 patients complete 6 induction cycles. The primary objective of the study is to evaluate the efficacy of the combination acalabrutinib + R-CHOP in terms of overall response rate (ORR), and the secondary objectives include time to response, duration of response, PFS, and overall survival, as well as the safety profile. The patients' quality of life will also be explored using the FACT-Lym and EORTC QLQ-C30 questionnaires. Results The trial received Clinical Trials Information System (CTIS) approval on June 16, 2025. The study is currently open for enrollment. No efficacy or safety results are available at the time of submission. Conclusions The SOUND-MCL study will provide the first evidence on the efficacy and safety of acalabrutinib in combination with R-CHOP, one of the standard-of-care options in first line for patients with newly diagnosed MCL not eligible for stem cell transplantation. Funding This study is sponsored by AstraZeneca Farmacéutica Spain, S.A. (Spain).