Background: Large B-cell lymphoma (LBCL) is characterized by genetic heterogeneity that confers a differential response to therapy. Pre-clinical models and clinical studies of BTK inhibitors (BTKi) in relapsed LBCL suggest preferential activity in ABC DLBCL (Wilson et al. Nat Med 2015). Further, ibrutinib with R-CHOP as frontline therapy is highly active in MCD and N1 genetic subtypes (Wilson et al. Cancer Cell 2021). Acalabrutinib (acala) is a BTKi with activity in LBCL but the full spectrum of untreated tumors that are BTKi-responsive remains unresolved. We designed a response-adapted study of acala as a window prior to frontline LBCL chemotherapy to investigate the molecular profile of BTKi-responsive tumors [NCT04002947].

Methods: Untreated LBCL (including transformed) pts were eligible if age ≥18, ≥stage II, PS ≤2, and adequate organ function. Pts with PMBL, unmeasurable lesions, or CNS disease were excluded. Pts first received acala 100mg twice daily x 14d in a window. All pts then received DA-EPOCH-R or R-CHOP; pts with ≥25% reduction by CT after the window continued acala 100mg BID on D1-10 of each cycle. Tumors were analyzed and molecularly classified by COO, LymphGen, and DZ signature. PET scans were analyzed by 2 radiologists blinded to outcomes. Plasma collected in Streck tubes at baseline, end of C2, at EOT, and during surveillance was analyzed by PhasED-Seq. The primary endpoint was the response (≥25%) rate of acala within LBCL subtypes. Secondary endpoints included safety and PFS/OS within LBCL subtypes.

Results: Of 110 pts screened, 99 enrolled and initiated acala. Median age was 60 (range 26-85) including 25% ≥70y. 60% were male and racial/ethnic groups included White (49%), Black (22%), Hispanic (17%), Asian (10%), and Native American (1%). 47% had IPI score ≥3 and 4% pts had HIV. Pathologic subtypes included 45 (45%) non-GCB DLBCL, 44 (44%) GCB DLBCL, 7 (7%) HGBL with MYC and BCL2, and 3 (3%) T-cell/histiocyte-rich LBCL. Eleven (11%) pts had transformed lymphoma. 98 pts were evaluable for acala response: 49 (50%) pts responded and 49 (50%) had no response. In non-responding pts, 47 (96%) received DA-EPOCH-R and 2 (4%) received R-CHOP. In responding pts, 27 (55%) received R-CHOP + acala while 22 (45%) received DA-EPOCH-R + acala. Acala responses occurred across pathologic subtypes including 20 (43%) GCB DLBCL, 8 (53%) ABC DLBCL, and 5 (83%) unclassified (UC). Both evaluable pts with THRLBCL had dramatic responses to acala. Of 52 pts with GCB/UC DLBCL, 22 (50%) with DZsig- tumors responded versus 2 (25%) with DZsig+. Acala showed responses in all LymphGen subtypes including 7 (100%) MCD/N1, 3 (60%) ST2, 9 (60%) EZB, 1 (50%) A53, 2 (33%) EZB-MYC, 6 (33%) BN2, and 15 (54%) Other. The toxicity of acala + R-chemo was mostly hematologic: G3/G4 neutropenia was seen in 8%/63% cycles of DA-EPOCH-R + acala and 7%/16% of cycles of R-CHOP + acala. G3/G4 thrombocytopenia was seen in 24%/17% of cycles of DA-EPOCH-R + acala and 7%/3% cycles of R-CHOP + acala. ≥G3 non-hematologic toxicities with acala + R-chemo included infection (22%), fatigue (6%), and hypotension (6%). No opportunistic infections occurred and 2 (4%) pts who received acala + R-chemo had atrial fibrillation. After a median follow-up of 39 months, the 2-year PFS/OS of all pts was 84.8% (76-91) and 87.8% (79-93), respectively. No survival difference was observed between acala responders and non-responders with 2-year PFS of 89.1% (76-95) vs 82.7% (68-91)(p=0.62) and 2-year OS of 90.7% (77-96) vs 86.8% (73-94)(p=0.59). By COO, the 2-yr PFS for GCB (N=46) was 93.3% (81-98), ABC (N=15) was 86.2% (55-96), and UC (N=7) was 83.3% (27-98)(p=0.29). Interestingly, pts with GCB tumors that were BTK-responsive had a 2-year PFS of 100% compared to 88.1% (68-96) in pts with GCB tumors that were BTK-resistant (p=0.12). Differences in the tumor microenvironment were not observed using deconvolution approaches, but in vitro experiments identified GCB models that showed decreased NF-kB expression after acala treatment. 2-year PFS for pts with a negative vs positive EOT PET scan was 92% (82-97) compared to 68% (44-83)(p=0.02).

Conclusions: Acala was universally active in MCD/N1 but also had clinical activity across COO and LymphGen genetic subtypes; In vitro experiments suggested a cell intrinsic survival role for BTK in GCB DLBCL. The toxicity profile of acala + R-chemo was safe in pts of all ages. Prognostic utility of interim and EOT MRD will be presented.

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2025
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