Intensive Chemotherapy and Immunotherapy, without Brain Irradiation, In Newly Diagnosed Patients with Primary CNS Lymphoma: Results of CALGB 50202

Whole brain irradiation is widely considered to be standard consolidative therapy in primary CNS lymphoma (PCNSL). However, concerns about the irreversible effects of brain irradiation on neurocognitive function, particularly in patients age > 60, have prompted interest in strategies to intensify induction and consolidative chemotherapy with the aim to eliminate or at least defer brain irradiation until relapse or progression. We present the results of the first Phase II multicenter trial, conducted by a major cooperative group within the United States, to evaluate an intensive chemotherapy-alone strategy in newly-diagnosed patients with PCNSL.

Induction chemotherapy consisted of methotrexate (MTX), temozolomide, rituximab (MT-R) with intravenous HD-MTX (8 gm/m2) administered every two weeks × 8 and rituximab adminstered weekly × 6. Temozolomide (150-200 mg/m2) was administered starting on day +7 and continued every 28 days × 5. Patients who achieved a CR received intensive consolidation cytarabine 2 gm/m2 BID on days 1–4 with infusional etoposide 40 mg/kg over 96 h (EA).

46 newly-diagnosed, immunocompetent patients with PCNSL were treated at 12 centers between 2005 and 2009. 96% of tumors were large B-cell lymphoma. Patient characteristics were as follows: median age was 60 (range 12–76), 47.8% were male, median ECOG PS was 1, 45.4% had involvement of deep brain structures, 47.7% had elevated CSF total protein, and 29.6% had increased serum LDH. 63% of patients exhibited CR to induction MT-R and went onto intensive consolidation (EA). With a median overall follow-up of 3.3 years, 21 out of 46 patients have exhibited disease progression and 15 patients have died. There was one treatment-related mortality (sepsis) during consolidation chemotherapy. There has been no evidence for significant early or delayed, treatment-related neurotoxicity. Median progression-free survival (PFS) is 2.3 years and estimated PFS with 95% confidence limits at 1, 2 and 3 years are 0.64 (0.48,0.76), 0.55 (0.39,0.69), and 0.50 (0.33,0.64). The estimated overall survival (OS) with 95% confidence limits at 1, 2 and 3 years are 0.73 (0.58, 0.84), 0.71 (0.55,0.81) and 0.67 (0.51,0.79). Notably, while the subgroup of patients with ECOG PS = 2 had inferior event-free survival (EFS) (p<0.018), the EFS was similar in patients older and younger than 60 (p<0.56).

CALGB 50202 demonstrates that induction chemotherapy with MT-R followed by EA consolidation is feasible in the multicenter setting and yields rates of PFS and OS in newly diagnosed PCNSL patients which are at least comparable to combined modality treatment that involves reduced or standard doses of whole brain irradiation. The MT-R-EA regimen is well-tolerated in patients age >60 and has similar efficacy in this population as in younger patients.

No relevant conflicts of interest to declare.