Correlates of response to combined checkpoint and BTK inhibition for treatment of richter transformation: Extended follow-up from the prospective RT1 trial

Abstract Background Richter transformation (RT), the development of diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL) in patients (pts) with chronic lymphocytic leukemia (CLL), remains a major challenge with poor prognosis. The phase II RT1 trial previously demonstrated high efficacy of the PD1 inhibitor tislelizumab with the BTK inhibitor zanubrutinib in pts with RT. Here, we present updated clinical data with extended follow-up and report translational analyses to identify biomarkers associated with response and survival. Methods Pts with histologically confirmed RT and ≤1 prior line of RT-directed therapy received tislelizumab (200 mg IV q3w) and zanubrutinib (320 mg orally QD). The primary endpoint was overall response rate (ORR) per Lugano 2014 after 6 cycles (21 days each). Pts with complete response (CR), partial response (PR) or stable disease continued treatment until progression. Secondary endpoints included progression-free survival (PFS), duration of response (DOR), time to next treatment (TTNT) and overall survival (OS). For translational analyses, primary RT tissue underwent 3′ RNA sequencing and whole-genome sequencing (WGS); gene expression, somatic mutations and copy number alterations were correlated with clinical outcomes. Results The full efficacy analysis population consisted of 48 pts of 57 enrolled pts. The median observation time was 25.7 months (interquartile range 12.4-41.3). At enrolment, the median age was 67 years (range 45-82). Overall, 46 (95.8%) pts had DLBCL-RT and 2 (4.2%) pts had HL-RT. In the CLL component, 17 (36.2%) pts had del17p/TP53mut, 29 (70.7%) pts had unmutated IGHV. Complex karyotype of CLL (≥3 aberrations, CKT) was detected in 16 (42.1%) pts. Central assessment showed 7 (14.5%) clonally unrelated 33 (68.8%) clonally related RT (8 [16.7%] unknown). Ten (20.8%) had prior RT-directed therapy. The most frequent adverse events were infections/infestations (86.0% of pts), gastrointestinal disorders (57.9%) and blood/lymphatic system disorders (52.6%). The study met its primary endpoint with ORR of 58.3% (95% CI 43.2-72.4, p=0.008), including 9 (18.8%) CR and 19 (39.6%) PR. In the efficacy population, the median DOR was 17.1 months, median PFS was 10.0 months (95% CI 3.5-16.5) and median TTNT (next-treatment or death) was 11.0 months (95% CI 1.7-20.4). A total of 24 pts received subsequent treatment, including 20 receiving CHOP-like therapy, and two received treatment with BCL2 inhibitors +/- BTK inhibitor. Overall, 8 pts underwent allogeneic stem cell transplantation (SCT) after study treatment or subsequent RT therapy. The median OS was not reached with a 2-year OS rate of 63.3%. PTS undergoing SCT had a median OS of 7.1 months (95% CI 6.0-8.2) from SCT until death. Baseline adverse risk factors significantly associated with PFS were severe constitutional symptoms, ECOG >0, CKT, elevated LDH, thymidine kinase and serum ß2-microglobulin (ß2M). For OS, risk factors were Binet C, severe constitutional symptoms, del17p/TP53mut, CKT, elevated LDH, thymidine kinase and ß2M. For DOR, risk factors were elevated LDH, del17p/TP53mut and CKT. BTK and PLCG2 resistance mutations were detected at relapse in peripheral blood of 11 pts, with 2 showing clonal expansion of pre-existing BTK C481S Variants. Further mutations emerged de novo at progression, with BTK C481S (n=9), L528W (n=1) and T474I (n=1), and PLCG2 comprising D993H (n=1) and A543D (n=1). In an exploratory gene expression analysis of RT tissue at baseline in 38 pts, responders showed significant enrichment of inflammatory gene sets, whereas non-responders exhibited enrichment of proliferative and oxidative phosphorylation pathways. Notably, PD-1/PD-L1 expression levels were not correlated with response. High expression of HSPD1, TMEM97, NOP56 and SLC39A4 was associated with non-response, while TRAF1 expression was linked to response and PFS. Among pts with long-term responses (up to 54 months), high TRAF1 expression, absence of CKT and lack of del17p/TP53mut were common features. Additional analyses will be presented at the meeting. Conclusion With extended follow-up, over 60% of pts of the efficacy population were alive at 2 years, and durable responses to tislelizumab plus zanubrutinib lasting beyond 3 years were observed. A distinct RT gene expression signature was associated with response, potentially enabling identification of pts most likely to benefit from combined checkpoint and BTK inhibition in RT.