Acalabrutinib Demonstrates Long-Term Activity in Relapsed/Refractory MCL


Acalabrutinib monotherapy continued to be highly active and safe in patients with relapsed/refractory mantle cell lymphoma with longer-term follow-up.

Michael Wang, MD

Michael Wang, MD

Acalabrutinib (Calquence) monotherapy continued to be highly active and safe in patients with relapsed/refractory mantle cell lymphoma (MCL), according to the final data from the phase 2 ACE-LY-004 trial (NCT02213926) presented during the 2021 Pan Pacific Lymphoma Conference.1

At a median follow-up of 38.1 months, the median overall survival (OS) with the selective second-generation BTK inhibitor was reached, at 59.2 months (95% CI, 36.5–not evaluable [NE]). In patients who received 2 or more prior therapies, the median OS was 55.9 months (95% CI, 27.7–NE), and was not yet reached (95% CI, 36.3–NE) in those with 1 prior therapy.

Acalabrutinib also elicited a high objective response rate (ORR) of 81% (95% CI, 74%-88%) among 124 patients, with a complete response (CR) rate of 48%, a partial response (PR) rate of 34%, and a stable disease rate of 8%. Notably, the ORR was not observed to be statistically different in patients who previously received 1, 2, or 3 or more therapies, at 83.1%, 86.5%, and 71.4%, respectively.

“This final report with a median follow-up of 38.1 months confirms that acalabrutinib is highly active in patients with relapsed/refractory MCL, with high response rates observed,” lead study author Michael Wang, MD, professor in the Department of Lymphoma & Myeloma at The University of Texas MD Anderson Cancer Center, said in a poster presentation on the data. “The median OS was reached, at 59.2 months, and it was consistent in different subgroups. The final results of ACE-LY-004 trial support the use of acalabrutinib in [these] patients.”

The FDA granted an accelerated approval to acalabrutinib as a treatment for adult patients with MCL after at least 1 prior therapy based on earlier data from this open-label, multicenter, phase 2 trial.2

To be eligible for enrollment, patients needed to be at least 18 years of age, have confirmed MCL with chromosomal translocation t(11;14)(q13;q32) and/or overexpression of cyclin D1, who were relapsed or refractory to at least 1 but no more than 5 prior treatments for their disease. Patients also needed to have measurable nodal disease and an ECOG performance status of 0 to 2. They could not have previously been exposed to BTK/BCL-2 inhibitors.

The primary end point of the trial was ORR per investigator assessment, and key secondary end points comprised investigator-assessed duration of response (DOR), progression-free survival (PFS), OS, and safety.

Among the 124 patients enrolled, the median age was 68 years (range, 42-90), 80% were male, 93% had an ECOG performance status of 0 to 1, 37% had bulky lymph nodes that were ≥5 cm, 72% had extranodal involvement, 75% had Ann Arbor stage IV disease, 24% had refractory disease, and 21% had blastoid/pleomorphic disease.

Additionally, 39% of patients had a Mantle Cell Lymphoma International Prognostic Index (MIPI) score that was low risk, 44% had a score indicative of intermediate risk, and 17% were high risk. The median number of previous systemic regimens received was 2 (range, 1-5). Moreover, 52% of patients had a Ki-67 proliferation index of less than 50%, and 26% had an index of 50% or higher.

The data cutoff date was December 4, 2020, and the median treatment exposure was 17.5 months (range, 0.1-65.3). A total of 18 patients were still receiving treatment at the time of the cutoff. The median dose intensity for all patients who received acalabrutinib was 99%.

The median DOR and PFS remained unchanged since a prior report on the data. The median DOR was 28.6 months (95% CI, 17.5-39.1), and the estimated 36-month DOR rate was 41.9% (95% CI, 31.7%-51.8%). The median PFS was 22.0 months (95% CI, 16.6-33.3), with an estimated 36-month PFS rate of 37.2% (95% CI, 28.2%-46.1%).

Additional data demonstrated that in the subgroup of patients who received 1 prior therapy (n = 59), the median OS was not yet reached (95% CI, 36.3–NE), with a 60-month OS rate of 53.1% (39.2%-65.2%). The median OS had also not been reached in those with a Ki-67 index of <50 (n = 70), in those who achieved a CR (n = 59), and in those who did not receive any subsequent anticancer therapy (n = 54). The 60-month OS rates in these subsets were 56.0% (95% CI, 43.1%-67.0%), 70.7% (95% CI, 57.2%-80.7%), and 59.9% (95% CI, 44.2%-72.5%).

Moreover, in those who previously received 2 or more cancer therapies (n = 65), the median OS was 55.9 months (95% CI, 27.7–NE), with a 60-month OS rate of 46.1% (95% CI, 33.1%-58.1%). The median OS was 40.3 months (95% CI, 27.2–NE) in those who did receive subsequent cancer therapies (n = 70), and these patients experienced a 60-month OS rate of 42.9% (95% CI, 31.2%-54.0%).

The median OS in the subsets of patients who achieved a PR (n = 42) and those who had a Ki-67 index of >50% (n = 26) was 37.8 months (95% CI, 24.4–NE) and 22.3 months (95% CI, 12.1–NE), respectively; the 60-month OS rates in these subgroups were 34.7% (95% CI, 19.6%-50.4%) and 33.5% (95% CI, 16.0%-52.0%), respectively.

The toxicity profile of acalabrutinib was consistent with what has previously been reported. Selected adverse effects (AEs) of clinical interest included atrial fibrillation (any-grade, 2.4%; grade 3/4, 0%), hypertension (any-grade, 4.0%; grade 3/4, 1.6%), hemorrhage (any-grade, 37.1%; grade 3/4, 4.0%), and infections (any-grade, 67.7%; grade 3/4, 16.9%).

The most common AEs experienced by at least 10% of patients included headache, diarrhea, fatigue, cough, myalgia, nausea, asthenia, constipation, upper respiratory tract infection, dyspnea, pyrexia, vomiting, anemia, dizziness, rash, contusion, sinusitis, abdominal pain, pneumonia, back pain, neutropenia, and arthralgia.

Additionally, 10.5% of patients experienced dose reductions, with 2.4% doing so because of toxicities. A total of 15 patients (12.1%) experienced treatment-emergent AEs that resulted in treatment discontinuation.


  1. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib monotherapy in patients with relapsed/refractory mantle cell lymphoma: final results from a phase 2 study. Presented at: 2021 Pan Pacific Lymphoma Conference; August 9-13, 2021; Big Island, HI.
  2. FDA grants accelerated approval to acalabrutinib for mantle cell lymphoma. News release. FDA. October 31, 2017. Accessed August 14, 2021.
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