Acalabrutinib with Rituximab Is Highly Effective First Line Treatment for Older Patients with Mantle Cell Lymphoma

Introduction – We previously reported the efficacy and safety results of a combination of ibrutinib with rituximab in patients (pts) with mantle cell lymphoma (MCL) ≥ 65 years. Due to the cardiac adverse events related to ibrutinib and favorable toxicity profile of acalabrutinib, we investigated the efficacy and safety of first line treatment with acalabrutinib and rituximab (AR) in pts MCL and performed comprehensive multiomic biomarker and minimal residual disease (MRD) profiling.

Methods – We enrolled 50 previously untreated pts in this single institution, single arm, phase 2 clinical trial – NCT05214183. Pts received acalabrutinib 100 mg orally twice a day and intravenous rituximab, weekly for first 4 weeks, followed by once a month for 12 months and subsequently once every 2 months totaling 24 months. Acalabrutinib was continuous for 24 months. The primary objective was to assess best overall response rate (ORR) rate after AR. Adverse events were coded as per CTCAE version 5. Clonoseq based MRD assessment was performed. Comprehensive genomic and immune landscape assessment was performed from serially collected peripheral blood, plasma, and MCL tissue biopsy specimens.

Results – Among 50 pts, the median age was 69 years (range: 65-81). Male:female ratio was 36:14. Forty-six pts had classic morphology, 3 had blastoid, and 1 was pleomorphic morphology. Ki-67% was available in 42 pts – 13/42 (31%) had high Ki-67% and 29/42 (69%) had a low Ki-67% (< 30%). Simplified MIPI risk stratification included: low (n=4), intermediate (n=35) and high risk (n=11). TP53 aberration status (mutations or deletion) was available in 43/50 pts and 12 pts had aberrant TP53.

Median number of AR cycles was 16 (range: 3-27). One pt was not evaluable for response at 12 weeks. After a median follow up of 28 months, the overall best response was 94% ORR and 90% CR, 4% PR; 6% were non-responders. Early responders were pts with complete metabolic response at end of 12 weeks 70% (35/50), and those with partial metabolic responses at the end of 3 months, were late responders, 18% (9/50). The primary study end point of 40% CR at end of 12 weeks was met. Twenty-eight patients were evaluable for MRD assessments up to 24 months. MRD assessments at 3, 6, 12, 18 and 24 months in evaluable patients, demonstrated an MRD negative rate of 50%, 58%, 73%, 87% and 83% respectively.

With a median follow up of 28 months, the median PFS and OS were not reached (2-year PFS 94%- and 2-year OS 96%). Fifteen pts (30%) came off study – 5 for adverse events (syncope, atrial fibrillation, intolerance, pneumonia, shingles), 3 for disease progression, 2 pt choice, one melanoma recurrence, 1 recurrent prostate cancer, 1 pancreatic cancer, 1 died of unknown etiology and one with an unusual chronic myelomonocytic leukemia. Overall, 3 pts died (2 on study with primary progression and another with unknown reason). The most common all-grade toxicities were fatigue (82%), myalgia (64%), headache (38%), bruising (28%) and <1% were grade 3 or higher. Among 50 pts, 1 pt had recurrence of grade 2 atrial fibrillation (2%) and one pt had recurrence of grade 3 unstable angina.

Using whole exome and bulk RNA sequencing, early responders had significant amplification of PI3KCA and TBL1XR1 genes and late responders exhibited TP53 mutations and BCL6 amplifications. Blood and tissue bulk RNA-seq detected significant reductions in SOX11 (p<0.0001) and B-cell gene expression (p=0.01) after treatment initiation, while multiparameter flow cytometry at 24 mos uncovered decreased B-cell content (p<0.0001) and increased monocytes (p=0.01). Serial B cell clonotype demonstrated a significant and persistent reduction at 3 months. Paired samples single cell RNA sequencing in primary refractory case demonstrated high fraction of exhausted CD8 T cells at progression. Differential analysis of cell populations revealed 35 and 28 cell populations were significantly increased in early and late responders, respectively (p<0.05). CD8 effector memory T cell populations were upregulated in late responders (n=9, p=0.01). Comprehensive immune landscape and plasma cytokines will be reported.

Conclusions – Chemotherapy-free frontline therapy with AR is highly effective, safe, induces deep MRD negative responses and alters immune landscape in older pts with MCL. Randomized studies are needed to confirm whether this regimen can be the new first line standard treatment for older MCL patients.