Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Long-Term Efficacy and Safety Results from a Phase 2 Study

Background: Acalabrutinib (acala) is a next-generation, highly selective, covalent Bruton tyrosine kinase (BTK) inhibitor approved for patients (pts) with mantle cell lymphoma (MCL) who have received ≥1 prior therapy. The efficacy and safety of acala in relapsed/refractory (R/R) MCL pts was demonstrated in a single-arm phase 2 study (ACE-LY-004; NCT02213926) after a median follow-up of 26 mo (Wang M, et al. Leukemia. 2019;33:2762-6). Here, we present results after an additional year of follow‑up.

Methods: Adults with MCL and ECOG PS ≤2 who had relapsed or were refractory to 1–5 prior therapies, had no prior BTK/BCL-2 inhibitor exposure, and did not require warfarin/vitamin K antagonists, received oral acala 100 mg twice daily until progressive disease (PD) or toxicity. Overall response rate (ORR; investigator-assessed partial response [PR] or better per Lugano classification), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety were assessed. Minimal residual disease (MRD) was analyzed in formalin-fixed, paraffin-embedded samples and peripheral blood by next-generation sequencing (5x10^-6) in pts with available paired samples.

Results: 124 pts were included (median age, 68 [range: 42–90] y; ECOG PS ≤1, 93%; bulky lymph nodes ≥10 cm, 8%; extranodal involvement, 72%; intermediate-/high-risk simplified MCL International Prognostic Index score, 44%/17%; median number of prior therapies, 2 [range: 1–5]; refractory disease, 24%).

After a median follow-up of 38.1 mo (range: 0.3–59.5), 24 (19%) pts remain on treatment and an additional 31 pts (55 total; 44%) remain in follow-up for survival. Of the 31 pts in post-acala follow-up, 6 remain PD-free (4 received post-acala treatment: anticancer treatment combinations and allogeneic stem cell transplant [n=3]; radiotherapy [n=1]). ORR was 81% (95% CI: 74, 88); 48% (95% CI: 39, 57) achieved complete response (CR). Median DOR was 28.6 mo (95% CI: 17.5, 39.1) and the estimated 36-mo DOR rate was 41.9% (95% CI: 31.7, 51.8). Median PFS was 22.0 mo (95% CI: 16.6, 33.3; Figure); estimated 36-mo PFS rate was 37.2% (95% CI: 28.2, 46.1). ORR and PFS were not significantly different between subgroups divided by Ki-67 index (≤50%, >50%); PFS also did not differ significantly by prior treatment regimen (bendamustine/rituximab [BR]-based, non-BR) or prior therapy line (1, 2, ≥3). Median OS was not reached; estimated 36-mo OS rate was 60.5% (95% CI: 51.1, 68.7). Of 30 MRD-evaluable pts, 6 (20%) achieved CR and undetectable MRD (uMRD) and maintained uMRD at last assessment.

The adverse event (AE) profile was largely unchanged with an additional year of follow-up. The most frequent AEs (≥20%) of headache (39%), diarrhea (37%), fatigue (30%), cough (23%), myalgia (22%), and nausea (22%) were primarily grade 1/2. Grade 3/4 AEs (≥5%) were neutropenia (11%), anemia (10%), and pneumonia (6%). Overall, 16 pts (13%) had cardiac AEs (11 with prior cardiac risk factors); 3 of the 16 pts had cardiac AEs in the last year of follow-up (grade 3/4: n=2). Overall, 6 pts (5%) had grade 3/4 cardiac AEs (acute coronary syndrome, acute myocardial infarction, complete atrioventricular block, cardiac failure, cardiorespiratory arrest, coronary artery disease, sinus arrest; n=1 each). One pt had grade 3/4 hypertension in the last year (total any grade, n=5 [4%]; total grade 3/4, n=2 [2%]). Five pts had bleeding AEs in the last year (n=46 [37%] total) including 2 with grade 3/4 AEs of gastrointestinal hemorrhage (n=2 total) and 1 with grade 3/4 subdural hematoma (n=1 total). Three pts had grade 3/4 infections in the last year (n=21 [17%] total).

Treatment discontinuation was primarily due to PD (n=74; 60%) and AEs (n=14; 11%). Seventeen AEs led to discontinuation in 14 pts; each AE occurred in only 1 pt. There were 57 deaths (46%), most commonly due to PD (n=38; 31%) or AEs (n=6; 5%); 14 deaths (11%) occurred in the last year of follow-up (PD, n=9; other, n=1; unknown, n=4). There were 6 deaths due to AEs (bilateral pulmonary embolism, critical aortic stenosis, myelodysplastic syndrome, pneumonia, suicide, non-small cell lung cancer); none were related to acala.

Conclusion: Extended follow-up demonstrates no emerging safety concerns for acala in R/R MCL pts. After a median of 38.1 mo, 19% of pts remain on acala. Overall, an estimated one-third of pts remain progression free at 36 mo, with median OS not yet reached. These data support long-term use of acala in R/R MCL pts.