Introduction: MCL is a rare B-cell non-Hodgkin lymphoma typically treated with first-line (1L) chemoimmunotherapy (CIT). While Bruton tyrosine kinase inhibitors (BTKis) are approved in CIT combinations in TN MCL, novel 1L chemotherapy-free BTKi combinations are of interest. The phase 1b ACE-LY-106 study supported development of acalabrutinib, venetoclax, and rituximab (AVR) in patients (pts) with TN MCL (Wang et al. Blood Adv. 2024;8:4539-48). We report preliminary AVR efficacy and safety in TN MCL in the ongoing, open-label, phase 2 TrAVeRse study (NCT05951959).

Methods: Pts were aged ≥18 y with TN MCL requiring treatment (tx), radiologically measurable disease, sufficient tissue for baseline clone detection for minimal residual disease (MRD) testing (clonoSEQ), and ECOG PS 0‒2 (or 3 if due to MCL). Pts received AVR induction (1 cycle [C] = 28 d): A (100 mg BID, C1‒C13 [+ C14 post induction]), V (C2‒C13, escalating during C2 [20 mg up to 400 mg daily]), and R (375 mg/m2 on day [D] 1 of C1‒12). Primary endpoint was MRD-negative (MRD-neg) complete response (CR) rate (MRD-neg in peripheral blood by next-generation sequencing [10-5; clonoSEQ], CR by 2014 Lugano criteria) at end of AVR induction (C13). Pts with MRD-neg CR at end of C13 were randomized 1:1 at C15D1 to continued A monotherapy until progressive disease (PD) or observation until PD with the option to restart A at relapse.

Results: In total, 108 pts were enrolled and treated in 7 countries (January–July 2024). Median age was 69 y (range 40–89) with 74.1% male and 87.0% White. Stage IV disease (90.7%), extranodal disease (93.5%), and marrow involvement (84.3%) were common. TP53 was mutated (TP53m) in 19.1% of pts (17/89 with available TP53), 30.6% had high-risk simplified MIPI score, 8.3% had blastoid/pleomorphic histology, and 38.0% had Ki-67 ≥30%.

At data cutoff (DCO; March 31, 2025 [14 mo after 1st pt treated]), response assessments were completed by 106 (98.1%) pts at C4D1, 100 (92.6%) at C7D1, 93 (86.1%) at C10D1, and 12 (11.1%) at C14D1 (end of AVR induction). Median follow-up was 10.5 mo (range 1–14); 102 (94.4%) pts remained on study, and 93 (86.1%) remained on tx. Median tx duration was 10.1 mo (range 1‒14). Fifteen pts (13.9%) discontinued ≥1 study drug; 11 (10.4%) discontinued all txs (AE, n=5; PD, n=4; pt decision, n=1; investigator decision, n=1). Four pts died (PD, n=3; AE, n=1).

At DCO, all 12 pts who had completed end of AVR induction response assessments achieved MRD-neg CR per Lugano criteria (primary endpoint). At time of DCO (most pts still on AVR induction), overall response rate was 95.4% (103/108); CR rates were 53.7% (58/108 per Lugano) and 63.0% (68/108 per PET-CT). Overall, 95.4% (103/108) achieved MRD-neg, including 76.9% (83/108) and 88.0% (95/108) at end of C3 and C6, respectively. Estimated 6-mo progression-free survival, overall survival, and duration of response rates were 97.1%, 98.1%, and 98.0%, respectively. Among the 17 pts with TP53m, 15 (88.2%) achieved objective response, 11 (64.7%) achieved CR, and 16 (94.1%) achieved MRD-neg any time during AVR induction; all 3 (100%) pts with TP53m who reached end of C13 achieved MRD-neg CR.

Tx-emergent AEs (TEAEs; AVR induction + C14) in ≥30% of pts were diarrhea (45.4%), headache (41.7%), and neutropenia (38.9%). G≥3 TEAEs occurred in 63 (58.3%) pts, most commonly (≥5 pts) neutropenia (n=29; 26.9%), pneumonia (n=8; 7.4%), neutrophil count decreased (n=7; 6.5%), and thrombocytopenia (n=6; 5.6%). Serious TEAEs occurred in 33 (30.6%) pts, most commonly (≥2 pts) pneumonia (n=6; 5.6%), febrile neutropenia (n=4; 3.7%), and fungal pneumonia, neutropenic sepsis, sepsis, and pyrexia (n=2 each; 1.9%). TEAEs led to death in 1 pt (non-small cell lung cancer). Tumor lysis syndrome (G2) was reported in 1 pt. Atrial fibrillation/flutter was reported in 3 pts (G1, n=1; G2, n=1; G3, n=1); ventricular arrhythmia (extrasystole) was reported in 1 pt (G2).Conclusion: At this early DCO in pts with TN MCL, with most pts yet to complete induction tx, AVR demonstrated rapid, deep responses, with high CR and MRD negativity rates overall and in pts with TP53m. Among pts who completed AVR induction, all achieved MRD-neg CR. AVR had an acceptable toxicity profile. At the time of submission, 73 (97.3%) of the 75 pts who have reached C15D1 achieved MRD-neg CR per PET-CT. Further update of fully validated results when all pts are expected to have completed AVR induction will be presented.

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2025
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