Phase I/II Study of Escalating Doses of Idarubicin in Combination with Methotrexate, Vindesine and Prednisolone in Patients with Primary Central Nervous System Lymphoma: Results of the GOELAMS LCP99 Multicenter Trial.

This study was performed to determine the maximum-tolerated dose (MTD) and the recommended dose (RD) of idarubicin in combination with methotrexate (MTX), vindesine (VDS) and prednisolone (PRED) given to previously untreated patients (pts) (60–70 years-old) with primary central nervous system lymphoma (PCNSL).

MTX and VDS were respectively given at the fixed dose of 3 g/m² (6-hour intravenous [IV]) and 3 mg/m² IV both on day 1. PRED was given at the fixed dose of 60 mg/m² (IV or per os) on day 1 to 5. Idarubicin was administrated IV on day 1 with doses starting at 12 mg/m2 and escalated by 2 mg/m² increments until MTD. Treatment was repeated every 3 weeks, three times. G-CSF was used. Intrathecal chemotherapy (MTX 15 mg, cytarabine 40 mg ) was performed on day 1. Subsequent whole brain irradiation (30 Gy + 10 Gy on residual mass) was performed. Limiting toxicity was defined as grade 4 neutropenia for more than 7 days or thrombopenia grade 4 or extra haematological toxicity more than grade 2.

Between 2000 and 2005, 35 immunocompetent pts (19 men, 16 women) with a new diagnosis of PCNSL received 87 cycles at four different idarubicin dose levels. At dose level 1 (12 mg/m²) and level 2 (14 mg/m²), only one of six developed a limiting toxicity. About 3 cases, no limiting toxicity was observed at level 3 (16 mg/m²). Three of six developed a limiting toxicity at level 4 (18 mg/m²) which was considered as MTD. Fourteen patients were enrolled at level 3 to confirm the data. At level 3, main haematological toxicities were neutropenia grade 3 (9%) or grade 4 (40%) and main extra haematological toxicities were infectious disease (5 % grade 3 or 4) and renal failure (grade 2: 9%). Median survival time was 385 days (IC95% 136–679).Overall response rate after radiotherapy was 65.7 % (15 CR, 7 PR).

Our study suggests that the RD of idarubicin administrated with MTX, VDS and PRED, should be 16 mg/m² on day 1 every 21-day cycle.

Delwail:Innate Pharma: Honoraria.