Fleming M, Huang Y, Dotson E, et al. - Since there is lack of clarity regarding the optimal timing for administering HDMTX when combined with (R)CHOP, researchers herein present their experience with HDMTX administered on day (D) 1 of (R)CHOP. Participants were 140 pts suffering from aNHLs managed from 2012–2020 with ≥1 cycle of HDMTX combined with (R)CHOP for prevention against (Cohort 1, n = 84) or treatment of (Cohort 2, n = 56) CNS involvement. HDMTX was involved in 54% of (R)CHOP cycles in Cohort 1 (242/445) and 90% in Cohort 2 (241/269), with a median number of HDMTX cycles/pt of 3 and 5, respectively. Premature cessation of (R)CHOP occurred in 7 pts (8%) in Cohort 1 and 16 (29%) in Cohort 2, most often because of toxicity in Cohort 1 (57%) and progression/death (69%) in Cohort 2. Treatment was delayed ≥7D in 11 cycles (3%) in Cohort 1 and 12 (6%) in Cohort 2. In this largest study focusing on the safety as well as deliverability of HDMTX administered on D1 of (R)CHOP, findings revealed uncommon occurrence of (R)CHOP treatment delays, dose reductions and discontinuations because of toxicities. The risk of neutropenic fever might be reduced by delaying prophylactic HDMTX beyond cycle 1 of (R)CHOP.