Prophylaxis with thiotepa and high-dose methotrexate showed lower central nervous system relapse rate in high-risk diffuse large B-cell lymphoma

Abstract

Abstract Background: Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) confers a dismal prognosis. Controversy exists regarding the optimal method of CNS prophylaxis in high-risk DLBCL. Although methotrexate (MTX) is the most widely used therapy for CNS prophylaxis, results from previous studies investigating systemic high-dose methotrexate or intrathecal methotrexate remain inconclusive. Therefore, additional strategies for preventing CNS relapse in DLBCL patients are required. We evaluated the efficacy and safety of different prophylactic regimens: thiotepa plus high-dose methotrexate (TT-HD-MTX), high-dose methotrexate (HD-MTX), or intrathecal methotrexate and cytarabine (IT) in newly diagnosed DLBCL patients with high-risk for CNS relapse. Methods We retrospectively analyzed all newly diagnosed DLBCL patients with high risk for CNS relapse (CNS risk score 4-6, CD5 positive, primary cutaneous DLBCL-leg type, or involvement of kidney, adrenal gland, breast, uterus, sinuses, or testicles) treated at Hunan Cancer Hospital between November 2009 and August 2024. Patients received either TT-HD-MTX (thiotepa 40 mg/m2, methotrexate 3.5 g/m2 for 2 cycles after the course of treatment), HD-MTX (methotrexate 3.5 g/m2 for 2 cycles after the course of treatment), or IT prophylaxis (4 doses during the course of treatment). The primary endpoint was the cumulative incidence of CNS relapse at 2 years, and the secondary endpoint was adverse events. Results A total of 245 newly diagnosed DLBCL patients (132 males; median age 60 years, range 19-76) with high-risk for CNS relapse were included. Of these, 173 patients were stage Ⅲ-Ⅳ disease, 36 had kidney or adrenal gland involvement, and 46 were CD5 positive. With a median follow-up of 30 months, the cumulative incidence of CNS relapse at 2 years was 16.7% (14/84) in the IT group, 10.0% (11/110) in the HD-MTX group, and 3.9% (2/51) in the TT-HD-MTX group. After multiple comparisons correction, no significant difference was observed between the IT and HD-MTX groups (P = 0.644). However, significant differences were observed between the TT-HD-MTX and HD-MTX groups (P = 0.0003), as well as between the TT-HD-MTX and IT groups (P = 0.0002). The most common adverse events included leukopenia (17.9% in the IT group, 50.9% in the HD-MTX group, and 52.9% in the TT-HD-MTX group), thrombocytopenia (14.3% in the IT group, 31.8% in the HD-MTX group, and 35.3% in the TT-HD-MTX group), and anemia (11.9% in the IT group, 27.3% in the HD-MTX group, and 29.4% in the TT-HD-MTX group). Grade 3-4 adverse events included leukopenia (2.4% in the IT group, 9.1% in the HD-MTX group, and 9.8% in the TT-HD-MTX group), thrombocytopenia (1.2% in the IT group, 4.5% in the HD-MTX group, and 5.9% in the TT-HD-MTX group), and pneumonia (2.4% in the IT group, 3.6% in the HD-MTX group, and 3.9% in the TT-HD-MTX group). No treatment-related deaths were reported. Conclusion Thiotepa plus high-dose methotrexate is an effective and well-tolerated CNS prophylactic regimen for high-risk newly diagnosed DLBCL patients. We are currently conducting prospective studies to validate these findings. Keywords Central nervous system prophylaxis; Diffuse large B-cell lymphoma; Thiotepa; High-dose methotrexate.