Phase II study of lenalidomide in combination with rituximab, cyclophosphadmie, doxorubicin, vincristine, and prenisone (R-CHOP) for central nervous system prophylaxis in high-risk diffuse large B cell lymphoma

Abstract Background Relapse of diffuse large B-cell lymphoma (DLBCL) in the central nervous system (CNS) is an uncommon but fatal event. The incidence is approximately 3–5% in all DLBCL patients following first-line treatment, reaching over 10% in high-risk patients, with a median survival of only 2–5 months from the diagnosis of CNS relapse. Historically, intravenous high-dose methotrexate (HD-MTX) has been recommended as CNS prophylaxis. However, accumulating evidence from recent studies has demonstrated that HD-MTX prophylaxis was not associated with reduced CNS relapse rates. This single-arm, open-label, phase II study aims to evaluate the efficacy, safety and feasibility of lenalidomide in combination with R-CHOP (R2-CHOP) as CNS prophylaxis in high-risk DLBCL patients. Methods Patients with newly diagnosed DLBCL were treated with lenalidomide 15 mg orally on days 1–14 of every 21-day cycle plus R-CHOP (rituximab 375 mg/m2 intravenous [IV] day 1, cyclophosphamide 750 mg/m2 IV day 1, doxorubicin 50 mg/m2 IV day 1, vincristine 1.4 mg/m2[maximum 2.0 mg total] IV day 1, and prednisolone 100 mg orally on days 1–5). For patients with poor general condition due to disease-related symptoms, lenalidomide could be skipped during the 1st cycle, and added from the 2nd cycle according to investigator's decision. Treatment was continued for 6 cycles, or until intolerance, inadequate response, disease progression, consent withdrawal, or death, whichever occurred first. Patients with high risk of CNS relapse were defined as those who had one or more of the following risk factors: (1) CNS-International Prognostic Index (CNS-IPI) ≥ 4, (2) involvement of testis, breast, adrenal gland, kidney, nasopharynx, or paranasal sinus, (3) double-expressor lymphoma with CNS-IPI ≥ 2, (4) double-hit lymphoma. The primary endpoint of this study was 2-year cumulative CNS relapse rate. Here, we report the interim safety and efficacy results of the study. Results A total of 100 patients enrolled in this study. The median age was 63 years (range, 25–83), and 60 patients were male (60.0%). Most patients had stage 3 or 4 disease (n=78, 78.0%), and 37 patients (37.0%) had CNS-IPI ≥ 4. Forty (40.0%) and 19 (19.0%) patients had double-expressor and double-hit lymphomas, respectively. High-risk site involvement was observed in 40 patients (40.0%), including testis (n=19), breast (n=9), nasopharynx or paranasal sinus (n=9), adrenal gland (n=10), and kidney (n=13). In 28 patients (28.0%), lenalidomide was added from the 2nd cycle. Treatment response was evaluable in 90 patients, and the best overall response rate and complete response rate were 96.6% and 82.2%, respectively. With a median follow-up duration of 15.4 months (95% CI, 12.2–18.5), the 1-year progression-free survival rate was 73.5% (95% CI, 64.1–84.3) and the 1-year overall survival rate was 87.7% (95% CI, 77.9–94.5). CNS relapse occurred in 6 patients, and the median time to CNS relapse was 8.7 months (range, 2.3–20.6). Among these 6 patients, 4 had CNS-IPI ≥ 4, and the other 2 had double-expressor lymphoma with CNS-IPI ≥ 2. The most frequent grade 3 or 4 adverse events were neutropenia (17.0%), followed by thrombocytopenia (13.0%), and anemia (9.0%). Febrile neutropenia was observed in 8 patients (8.0%). Conclusion R2-CHOP demonstrated high response rates and favorable survival outcomes in DLBCL patients at high risk of CNS relapse. The regimen showed a favorable safety profile with manageable toxicities. Longer follow-up is needed to evaluate the efficacy of R2-CHOP in preventing CNS relapse.