Long-term clinical outcomes from the smart start trial: Rituximab, lenalidomide and ibrutinib in patients with newly diagnosed large B-cell lymphoma

Abstract Background Approximately 30-40% of patients (pts) with diffuse large B-cell lymphoma (DLBCL) develop relapsed or refractory (r/r) disease after frontline therapy. Harnessing targetable biological vulnerabilities, the Smart Start trial served as a proof-of-concept for a frontline noncytotoxic combination regimen utilizing rituximab, lenalidomide and ibrutinib (RLI regimen) and demonstrated promising outcomes at initial follow-up. Herein, we present the updated analysis of the long-term outcomes of safety and efficacy of the Smart Start trial (PMID 35952327). Methods This was an investigator-initiated, open-label, single-center, phase II clinical trial investigating pts with untreated non-germinal center B-cell (non-GCB) DLBCL. Pts received two cycles of RLI (rituximab 375 mg/m2 IV day 1, lenalidomide 25 mg daily orally days 1-10, ibrutinib 560 mg orally daily; pts>65 years (yrs) could receive ibrutinib 420 mg per amended protocol) followed by chemotherapy (R-CHOP or R-EPOCH) for cycles 3-8 along with continued RLI. Results 60 pts were enrolled from May 2016 until February 2019. The median age was 63.5 yrs, with 28% of pts being older than 70 yrs, and 42% (25/60) considered poor risk per Revised International Prognostic Index. The median time from diagnosis to treatment was 28 days (range, 9-138 days). Two pts withdrew consent prior to starting therapy and were only evaluable for safety. Two pts only received two cycles of RLI-alone; one withdrew consent after a complete response (CR) and one due to progression of disease (PD) and central nervous system aspergillosis. Fifty-six pts received RLI combined with chemotherapy (EPOCH: n=31; CHOP: n=25). Of note, one pt had preplanned radiation to the contralateral testicle after completing study therapy with a CR, and one patient switched from EPOCH to RCHOP based on treating physician preference. With a median follow-up of 77.1 months (range, 2.4-103.0), the median progression-free survival (PFS) and overall survival (OS) were not reached. At 6-yrs, PFS was 84% (95% CI, 74-94%), and OS was 91% (95% CI, 84-99%). A total of six death events occurred - three additional deaths since the original publication. Three of six deaths were determined to be lymphoma-related, either secondary to PD (n=1) or infectious complications in the setting of treatment (n=2). The remainder (n=3) were secondary to metastatic breast cancer (n=1) and unknown causes (n=2). Seven pts were determined to have PD during the updated entire follow-up period. Most events occurred early (<2 yrs after treatment), while two PD events occurred at 47 and 70 months. Pathology results (available in four pts) demonstrated a r/r B-cell lymphoma (BCL) in all pts (high-grade BCL: n=1; GCB BCL with anaplastic features: n=1; non-GCB DLBCL: n=1; BCL, not otherwise specified: n=1). One pt who received only 2 cycles of RLI-alone remains in CR after 86 months. Among five pts with treatment details available after PD, three pts received autologous stem cell transplant, and two pts received a CD19-directed chimeric antigen-receptor T cell therapy. On safety analysis, the most common adverse events during treatment included nausea (all grades: 85%, grade ≥3: 3%), peripheral sensory neuropathy (all : 83%, grade ≥3: 8%), diarrhea (all grades: 78%, grade ≥3: 13%) and mucositis (all grades: 75%, grade ≥3: 3%). Furthermore, the most common grades 3 or higher were neutropenia (53%), thrombocytopenia (47%) and anemia (38%). Febrile neutropenia occurred in 37%. No new long-term safety signals were observed from the addition of RLI. Two pts developed reduced ejection fraction heart failure, attributed to anthracycline exposure (n=1) and atherosclerotic coronary artery disease (n=1). Furthermore, one pt developed chronic phase chronic myeloid leukemia. Conclusion This updated analysis of the Smart Start trial establishes the robust long-term safety and durability of incorporating RLI into the frontline treatment of pts with newly diagnosed DLBCL. Although direct comparisons cannot be made, numerically improved survival outcomes were observed compared to historical cohorts treated with R-CHOP alone (GOYA trial - 5-year PFS of 62.6% and OS of 77.7%; Sehn et al, 2020). These promising findings indicate that the integration of innovative targeted therapy strategies for the frontline management of DLBCL should be assessed in larger, later-phase trials.