Polatuzumab Vedotin, Rituximab and Lenalidomide (Pola-R2) As First-Line Therapy for Unfit and Frail Elderly Diffuse Large B-Cell Lymphoma Patients: Preliminary Result of a Prospective, Phase II, Multi-Center Study

Introduction: Diffuse large B-cell lymphoma is a common cancer in elderly patients while treatment for this entity was not standardized, especially for those who were unfit or frail according to comprehensive geriatric assessment (CGA). R-miniCHOP in patients older than 80 years yielded a CRR+CR_uR of 63% but limited by its toxicity (Frédéric Peyrade et al., Lancet Oncol, 2011). Other chemo-free regimens, such as rituximab plus lenalidomide (R²), or combined Bruton kinase inhibitors, rituximab and lenalidomide (R²+BTKi) showed fewer toxicities, but compromised on efficacy (Guido Gini et al., Blood, 2023; Pengpeng Xu et al., Lancet Healthy Longev, 2022; Haiyan Yang et al., ASH 2022). As polatuzumab vedotin was approved in China for first-line DLBCL and was reported to have synergistic effect with rituximab (Natsumi Kawasaki et al., Br J Haematol, 2022), we conducted a prospective, phase II, multi-center study to explore the efficacy and safety of polatuzumab vedotin plus rituximab and lenalidomide(Pola-R²) in treatment-naive patients ≥70 years old and defined as unfit or frail (named non-fit) by CGA (NCT06176729).

Methods: Newly diagnosed DLBCL patients aged over 70 years old and categorized to unfit or frail group by CGA were enrolled. All patients were plan to receive a maximum of eight 21-day cycles of pola-R² regimen. Polatuzumab vedotin was administered at a dosage of 1.8mg/kg intravenously on day 1, rituximab 375mg/m² intravenously on day 1 and lenalidomide 25mg once daily orally on day 1 to day 14. Interim evaluation by ¹⁸F-FDG PET/CT scan was planned after four cycles. Patients achieving PR/CR would move on to receive another 4 cycles of treatment and then go into follow-up phase. Circulating tumor DNA (ctDNA) assay was scheduled at baseline, after C2,C4 and C8. Treatment response was assessed by 2014 Lugano response criteria. Adverse events were graded by CTCAE 5.0. The primary endpoint was complete response rate (CRR) at end-of-treatment (EOT) by PET/CT. The secondary endpoints are ORR, 2-year progression-free survival (PFS), 2-year overall survival and safety.

Results: Twenty-one patients were enrolled in our study until Jul 20, 2024. Median age was 79.5 years (range: 73-90) with four patients defined as frail by CGA. Four(19.0%) and fourteen(66.7%) patients were in Ann Arbor stage III and IV, respectively. Ten(47.6%) patients had an international prognosis index (IPI) score of 4-5 and three patients had bulky disease. Thirteen(61.9%) patients were classified non-GCB type according to cell of origin by Han’s classifier. Eight(38.1%) patients had double-expression lymphoma. Fourteen patients had baseline circulating DNA (ctDNA) assessment, mutations of interest such as MYD88, CD79B and TP53 were found in 4(28.6%), 4(28.6%), and 3(21.4%) patients, respectively. After a median follow up of 6 months, eight patients had finished treatment and the EOT CRR was 100%. Fourteen patients had PET/CT assessment results after 4 cycles of Pola-R², one patient dropped out because of disease progression and all other patients achieved CR. The CRR after 4 cycles of Pola-R² regimen were 92.9%. Eight patients had continuous monitor of ctDNA and all of them reached an undetected minimal residual disease at a level of 10^-4 (uMRD4) after cycle4. The most common grade 3 to 4 AE was neutropenia (7patients, 33.3%). Covid19 infection(grade2) and upper respiratory tract infection(grade2) occurred in two and one patient respectively. Other side effects including skin rash (3 patients), peripheral neuropathy (3), fatigue(2), atrial fibrillation(1), aspartate aminotransferase(1) and creatinine(1) elevation were all grade 1-2. No patients died during our study period.

Conclusion: Based on these results of our study, Pola-R² regimen was highly effective and safe in previously untreated non-fit elderly DLBCL patients. ctDNA monitoring indicated the response was deep. But longer follow-up is needed to confirm the response is durable. Results of this phase II trial (NCT06176729) are worth expecting.