Acalabrutinib and Rituximab in Elderly Patients with Newly Diagnosed Mantle Cell Lymphoma Including a Matched Population-Based External Comparator- the Nordic Lymphoma Group NLG-MCL8 (ALTAMIRA) Phase II Trial

Introduction: Although most patients with mantle cell lymphoma (MCL) are elderly, there is no universal established standard therapy for this population. Accumulating evidence show that BTK inhibitors may have an important role in front line regimens. Ibrutinib+ rituximab was recently compared to chemoimmunotherapy in the phase 3 ENRICH trial, but in vitro suggest that ibrutinib partially antagonizes the activity of rituximab through NK-cell inhibition. Acalabrutinib is not associated with NK-cell inhibition potentially and may thus be a more attractive combination partner with rituximab (AR). In this multicenter open-label phase II trial, we evaluated safety and efficacy of AR in elderly patients with MCL, including an MRD guided treatment duration strategy, as previously explored in the NLG-MCL7 (VALERIA) trial.

Methods: Main eligibility criteria were age ≥60 years, untreated MCL, non-eligible for transplant, WHO PS 0-3, and measurable disease by imaging. The primary endpoint was progression-free survival, and to provide a context for the single arm trial, an external comparator cohort was created using data were compared to a matched dataset from the population-based Swedish MCLcomplete project enrolling 1367 patients treated in the period 2006-2018. Matching was done by matching on sex and using nearest neighbor on MIPI score, in a 1:5 ratio for MCLcomplete. The most common regimens in the matched dataset were R-Bendamustine (33%) and NLG-MCL2 (18%). Minimal residual disease (MRD) monitoring by RQ-PCR was performed every 3 months during follow-up, according to EuroMRD criteria. Sequencing of the most frequently mutated genes in MCL was performed on formalin-fixed tumor tissue.

Treatment schedule: Acalabrutinib 100 mg BID in combination with rituximab 375 mg/m2 IV on day 1 every 28 days for 6 cycles, followed by treatment every 8 weeks. The minimum duration of treatment was 13 months. Patients in molecular remission in blood and bone marrow and in complete remission, would stop acalabrutinib, but continue with rituximab for up to 36 months. Patients with TP53 aberrations and/or blastoid histology continued with treatment until progression or unacceptable toxicity regardless of MRD results.

Results: In total, 81 patients were enrolled, from 18 sites in Sweden, Norway, Denmark, Finland and South Korea. The median age was 75 years, 61 (75%) were male and 56 (69%) were MIPI high risk. A TP53 mutation was detected in 19 (24%) of diagnostic biopsies, high Ki67 expression (>30%) in 18 (22%), and blastoid histology in 5 (6%). At 6 months, the ORR (n=61) was 95% (37 CR, 21 PR). The median follow-up is currently 15.5 months. PFS at 1 year is 86.5% (95% CI 78.9-94.8) , compared to 71.8% (95% CI 69.5-74.2) in MCLcomplete (p=0.016). OS at 1 year is 92.9% (95% CI 87.1-99.2) compared to 79.6% (95% CI 77.5-81.7) in MCLcomplete (p=0.012). Patients with TP53-mutated disease showed inferior outcome with a PFS of 69% at 1 year. At 12 months, 27 (59%) of 46 evaluable patients were MRD-negative, 14 were MRD+, 2 were not evaluable by MRD, and 3 are awaiting results. 19 out of 27 MRD-neg (70.4%) have stopped acalabrutinib at this point, and 5 continued treatment due to high risk biology. Another 2 patients stopped acala at 18 months, and one pt at 24 months, due to MRD-negativity. The most common grade 3-4 AE were neutropenia in 11 pts, infection in 10 pts, and cardiovascular toxicity in 7 pts. There have been 9 deaths, 3 due to MCL, 2 due to treatment-related toxicity (aplastic anemia and sepsis), and 4 due to other causes.

Conclusions: A response adapted treatment strategy, by stopping treatment in molecular remission appears to be feasible in MCL, even in an international multicenter trial setting. By comparison to matched population-based data, single arm clinical trial data may be set into a meaningful context, and frontline AR appear to be favorable compared to current standard therapy. Updated results will be presented at the meeting, including prolonged follow-up of MRD-negative patients after stopping acalabrutinib.