Timing of high-dose methotrexate CNS prophylaxis in DLBCL: an analysis of toxicity and impact on R-CHOP delivery

Abstract

High-dose methotrexate (HD-MTX) is increasingly used as prophylaxis for patients with diffuse large B-cell lymphoma (DLBCL) at high risk of central nervous system (CNS) relapse. However, there is limited evidence to guide whether to intercalate HD-MTX (i-HD-MTX) between R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone given at 21-day intervals) or to give it at the end of treatment (EOT) with R-CHOP-21. We conducted a retrospective, multicenter analysis of 334 patients with DLBCL who received CNS prophylaxis with i-HD-MTX (n = 204) or EOT HD-MTX (n = 130). Primary end points were R-CHOP delay rates and HD-MTX toxicity. Secondary end points were CNS relapse rate, progression-free survival, and overall survival. The EOT group had more patients with a high CNS international prognostic index (58% vs 39%; P < .001) and more concurrent intrathecal prophylaxis (56% vs 34%; P < .001). Of the 409 cycles of i-HD-MTX given, 82 (20%) were associated with a delay of next R-CHOP (median, 7 days). Delays were significantly increased when i-HD-MTX was given after day 9 post–R-CHOP (26% vs 16%; P = .01). On multivariable analysis, i-HD-MTX was independently associated with increased R-CHOP delays. Increased mucositis, febrile neutropenia, and longer median inpatient stay were recorded with i-HD-MTX delivery. Three-year cumulative CNS relapse incidence was 5.9%, with no differences between groups. There was no difference in survival between groups. We report increased toxicity and R-CHOP delay with i-HD-MTX compared with EOT delivery but no difference in CNS relapse or survival. Decisions on HD-MTX timing should be individualized and, where i-HD-MTX is favored, we recommend scheduling before day 10 of R-CHOP cycles.

Ineffectiveness of high‐dose methotrexate for prevention of CNS relapse in diffuse large B‐cell lymphoma

“…The results of our study are important as they cast doubt upon the utility of prophylactic HD‐MTX, a resource‐intensive therapy which requires hospital admission and increases the risks of toxicity and treatment delays. Indeed, a recent retrospective multicenter study reported clinically relevant rates of R‐CHOP treatment delays (20%), mucositis (10%), febrile neutropenia (10%), and renal toxicity (5%) with intercalation of HD‐MTX between R‐CHOP cycles 10 . Given these risks of toxicity and the lack of meaningful benefit observed in our high‐risk study population, we question whether prophylactic HD‐MTX should continue to be routinely recommended for patients with DLBCL.…”

“…National Comprehensive Cancer Network (NCCN) and British Society for Hematology (BSH) guidelines recommend CNS prophylaxis with the addition of intravenous (IV) high‐dose methotrexate (HD‐MTX) to standard chemoimmunotherapy for high‐risk patients 8,9 . However, HD‐MTX requires inpatient admission with careful volume status and drug level monitoring, and carries with it risks of mucositis, renal dysfunction, myelosuppression, infection, and treatment delays 10 . Furthermore, the effectiveness of HD‐MTX for CNS prophylaxis has never been studied in well‐designed prospective clinical trials.…”

“…Furthermore, the effectiveness of HD‐MTX for CNS prophylaxis has never been studied in well‐designed prospective clinical trials. Small retrospective studies have suggested favorable outcomes with prophylactic HD‐MTX compared to historical or contemporary controls, but more recent observational studies found no benefit of HD‐MTX on preventing CNS relapse 10‐15 . Despite the limited evidence supporting the use of prophylactic HD‐MTX, many centres – including our own – adopted this practice in hopes of improving outcomes for this high‐risk patient population.…”

Feasibility of high-dose methotrexate administered on day 1 of (R)CHOP in aggressive non-Hodgkin lymphomas

“…In most published studies on the use of HDMTX concurrently with R-CHOP in which the timing of HDMTX administration was reported, HDMTX was administered mid-cycle, on day 10-15 following R-CHOP. 6,[13][14][15][16] This interposition of methotrexate and other antimetabolites between chemotherapy cycles (including CHOP) in NHL dates back to more than four decades. To improve the efficacy of standard treatments, the antimetabolites, which are most effective during the S-phase of cell division, were added between chemotherapy cycles when the tumor burden is reduced and cells are in the logarithmic growth phase.…”

High-dose methotrexate is effective for prevention of isolated CNS relapse in diffuse large B cell lymphoma

“…However, evidence supporting this practice is limited to small retrospective studies [ 6 , 7 ], and recent studies demonstrate no benefit of HDMTX in preventing CNS relapse [ 8 , 9 ]. Given the potential for HDMTX to be associated with significant toxicity and delays of RCHOP chemotherapy which may compromise systemic control [ 10 ], further evaluation of the role of HDMTX in mitigating the risk of CNS recurrence is warranted.…”