Ambulatory high-dose methotrexate administration as central nervous system prophylaxis in patients with aggressive lymphoma

S Bernard,C Madaoui,L Hachon,L Aguinaga,Catherine Thieblemont,Emeline Perrial,J F Diasonama,P Brice,E Miekoutima,H Moatti,I Madelaine

doi:10.1007/s00277-020-04341-7

Abstract

High-dose methotrexate (HD-MTX) at 3 g/m2 is one of the strategies for central nervous system (CNS) prophylaxis in the first-line treatment of aggressive lymphomas, especially in diffuse large B cell lymphoma patients with high-risk CNS-International Prognostic Index. The objective of our study was to retrospectively analyze the safety of 2 cycles of systemic HD-MTX administered as an ambulatory regimen. Between January 2013 and December 2016, 103 patients were carefully selected on 6 criteria, including age < 60, albumin > 34, performance status 0 or 1, normal renal and hepatic functions, good understanding of practical medical guidance, and no loss of weight. Strict procedures of HD-MTX infusion were observed including alkalinization, urine pH monitoring, and leucovorin rescue. Renal and hepatic functions were monitored at days 2 and 7. MTX clearance was not monitored. Toxicities and grades of toxicity were collected according to the NCI-CTCAE (version 4.0). Among the 103 selected patients, 92 (89%) patients successfully completed the planned 2 cycles of HD-MTX on an outpatient basis. Eleven patients completed only 1 cycle, 3 because of lymphoma progression and 8 because of toxicity including 3 grade II hepatotoxicity, 2 grade I/II renal toxicity, 1 grade III neutropenia, 1 active herpetic infection, and 1 grade III ileus reflex. Reported adverse events (AE) included 92 (84%) grade I/II and 18 (16%) grade III/IV. Grade III hepatotoxicity, mostly cytolysis, was the most frequent AE observed with 8 (8%) events. Grade III/IV hematologic toxicities concerned 9 patients with 8 grade III/IV neutropenia and 1 thrombocytopenia. Renal toxicity was rare, mild, and transient, observed with 4 (4%) grade I/II events. Ambulatory administration of HD-MTX at 3 g/m2 without MTX clearance monitoring is safe with strict medical guidance. It requires careful selection of patients before administration, and a renal and hepatic monitoring after the administration.

Highlights

central nervous system (CNS) relapse is a serious event in patient with aggressive nonHodgkin lymphoma (NHL) and associated with poor outcomes
All these patients were treated as first-line treatment with CHOP or ACBVP, in association with anti-CD20 for B cell lymphoma and were eligible for high-dose methotrexate (HD-MTX) to benefit of CNS relapses prophylaxis [11]
CNS relapse prophylaxis was administrated to all patients with ageadjusted IPI (aaIPI) ≥ 1 in (R)-ACBVP arm of treatment and as assessed by the practitioner for patients receiving (R)-CHOP based on known risk factors

Summary

Introduction

CNS relapse is a serious event in patient with aggressive nonHodgkin lymphoma (NHL) and associated with poor outcomes. The value of prophylactic intrathecal chemotherapy is controversial since CNS relapses occur more frequently in brain parenchyma than in meninges and may be observed in patients who have received intrathecal chemotherapy [1, 8]. More aggressive CNS prophylaxis such as systemic high-dose methotrexate (HD-MTX) at > 3 g/m2 seems to be the best alternative in this context [9]. This strategy has been developed in the LYSA group since 1989, after an induction regimen including 4 cycles of intensified CHOP for patients with aggressive

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