A phase 1 dose escalation study of idarubicin combined with methotrexate, vindesine, and prednisolone for untreated elderly patients with primary central nervous system lymphoma: The GOELAMS LCP 99 trial

Abstract

Treatment of primary central nervous system lymphoma (PCNSL) in elderly patients remains unsatisfactory. To develop a new high-dose methotrexate (HD-MTX)-based regimen including idarubicin, a phase 1 multicenter dose escalation study was conducted to determine the maximum-tolerated dose (MTD) of idarubicin. Thirty-five immunocompetent patients with PCNSL were enrolled. The median age was 65 years (range, 60-70 years). MTX and vindesine (VDS) were given at the fixed dose of 3 g/m 2 (6-hr intravenous [IV]) and 3 mg/m 2 IV on day 1, respectively. Prednisolone (PRED) was given at the fixed dose of 60 mg/m 2 (IV or orally) on days 1-5. Idarubicin was escalated in increments of 2 mg/m 2 with doses ranging from 12-18 mg/m 2 IV on day 1. Treatment was repeated three times every 3 weeks. Dose-limiting toxicity (DLT) was defined as grade 4 neutropenia for more than 7 days, thrombocytopenia grade 4 or nonhaematological toxicity more than grade 2. The MTD of idarubicin was reached at 16 mg/m 2 . At this level, the main haematological toxicities were thrombocytopenia grade 4: 5% and neutropenia grade 3 or 4 (52%); the main nonhaematological toxicities were grade 3 or 4 infectious disease (5%) and grade 2 renal failure (9%). For the study population, median overall and progression-free survival were 19 and 13 months, respectively. Our study suggests that the MTD of idarubicin in combination with HD-MTX, VDS, and PRED, should be 16 mg/m 2 . Further studies will be necessary to challenge a standard treatment in elderly patients with PCNSL.

High-dose methotrexate-based immuno-chemotherapy for elderly primary CNS lymphoma patients (PRIMAIN study)

“…Based on a recent systematic review, 7 only few prospective multicentre studies focussing on elderly patients with PCNSL have been reported, 14, 15, 16, 17, 18, 19, 20 which all used HD-MTX-based chemotherapy. However, no standard protocol has yet been defined and there was no study that used rituximab.…”

Methotrexate plus idarubicin improves outcome of patients with primary central nervous system lymphoma

“…[ 31 ] Unfortunately, this recommendation was not supported by other clinical trials. [ 30 , 35 , 36 ] Thus, in the current study, we used a median IDA dose of 8.5mg/m 2 . Further studies are needed to establish the standard dosage for IDA.…”

High-dose thiotepa-based chemotherapy with autologous stem cell support in elderly patients with primary central nervous system lymphoma: a European retrospective study

“…Based on a recent systematic review, 9 a limited number of prospective multicentre studies focussing on elderly PCNSL patients has been reported. 8,[17][18][19][20][21] Most of the studies included HD-MTX in combination with partner chemotherapy agents, but to-date no standard protocol has been defined. Acknowledging the limitations of intertrial comparison, the best reported response rate was 79% but the corresponding 1-year PFS was only 36%.…”