Clinical Relevance of the Dose of Cytarabine In the Treatment of Primary CNS Lymphomas with Methotrexate-Cytarabine Chemotherapy Combination

The combination of high doses (HD) of methotrexate (MTX) and cytarabine (ara-C) (experimental arm of the IELSG #20 trial) is the standard upfront chemotherapy for patients ≤75 years old with primary CNS lymphomas (PCNSL) [Ferreri AJM, et al. Lancet 2009; 374:1512–20]. The addition of an alkylating agent could improve MTX-ara-C efficacy since these drugs are active against quiescent G0 cells and increase antimetabolites cytotoxicity. Thus, patients with PCNSL diagnosed in 2008 at five Italian and one Swiss centers were treated with a combination of HD-MTX, HD-ara-C and thiotepa (MAT regimen). With respect to the conventional MTX-ara-C combination, ara-C dose was reduced from 2 g/m² to 1 g/m² to minimize the risk of toxicity. Herein, we report tolerability, activity and efficacy of MAT regimen.

HIV-negative patients with PCNSL diagnosed during 2008 and selected by using the same eligibility criteria of the IELSG #20 trial (age 18–75, ECOG-PS ≤3, measurable disease) were considered. Patients received four courses (interval 3 weeks) of MTX 3.5 g/m² d1 + ara-C 1 g/m² × 2/d, d2-3 + thiotepa 30 mg/m² d4, followed by whole-brain irradiation (WBRT). Thirty-nine patients treated with MTX/ara-C combination and WBRT in the IELSG #20 trial were used as controls.

Twenty patients (median age 57 ys; range 42–74) were treated with MAT regimen. No significant differences in patient characteristics between MAT and MTX-ara-C groups were observed (Table). The comparison between MAT and MTX/ara-C regimens did not show any significant difference in terms of actually delivered courses (69% vs. 76%), chemotherapy interruption (65% vs. 44%), dose reductions (60% vs. 44%), G4 neutropenia (85% vs. 74%), G4 thrombocytopenia (85% vs. 64%), infections (45% vs. 30%), G4 non-hematological toxicity (15% vs. 8%), and toxic deaths (5% vs. 8%). Median relative dose intensity of MTX (75% vs. 77%) and ara-C (67% vs. 68%) were identical in MAT and MTX+ara-C combinations, but median dose intensity of ara-C was 898 mg/m²/week and 1.808 mg/m²/week, respectively.

Response after MAT chemotherapy was complete in four patients (CRR: 20%; 95%CI: 3%-37%) and partial in three (ORR: 35%; 95%CI: 15%-55%), which were significantly lower with respect to those reported with MTX/ara-C combination (Table). The seven patients who responded to MAT received consolidation WBRT, with early progressive disease (PD) in three cases and systemic dissemination in one; only four of the 12 patients with PD after MAT received WBRT, without any benefit in three of them.

At a median follow-up of 23 months, 17 (85%) MAT patients experienced failure (PD, relapse, death), with a 2-yr PFS of 20±9%, which is significantly worse with respect to those reported with MTX/ara-C (Table). Five patients treated with MAT and 18 treated with MTX/ara-C are alive, with a 2-yr OS of 23±9% and 56±8%, respectively.

Tolerability of MAT regimen was similar to those reported with MTX-ara-C combination. Conversely, ara-C dose reduction was associated with a remarkably lower activity and efficacy, hiding a potential benefit of the addition of thiotepa. Four doses of ara-C 2 g/m² per course are recommended in the upfront treatment of PCNSL.

No relevant conflicts of interest to declare.