High-Dose Combination Therapy Improves Outcomes in CNS Lymphoma

A complex, high-dose combination therapy is tolerable and effective in patients with relapsed B-cell lymphoma that has spread to the central nervous system (CNS), according to results of a phase II trial. The treatment studied consisted of cytarabine and methotrexate at high-doses, followed by rituximab plus high-dose sequential chemoimmunotherapy (R-HDS) and autologous stem-cell transplantation (ASCT).

Progression of B-cell lymphoma to the CNS is rare but can occur early in the course of aggressive disease and is difficult to treat. The study was published in the Journal of Clinical Oncology.

Based on prior studies of treatments for CNS-disseminated B-cell lymphoma, Andrés J. M. Ferreri, MD, of the lymphoid malignancies unit at the San Raffaele Scientific Institute in Milan, Italy, and colleagues tested the novel three-part, radiation-free combination regimen.

Patients were treated with a two-course induction of high-dose methotrexate and cytarabine plus rituximab and intrathecal liposomal cytarabine. Patients with bulky, systematic disease at diagnosis could also be treated with 1 or 2 cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Patients who had progression or stable disease went on to receive salvage therapy. Patients who achieved a complete or partial response after induction then received intensification of R-HDS (cyclophosphamide, cytarabine, and etoposide) at 4-week intervals. Patients with a complete or partial response after the intensification phase were referred for an ASCT. Autologous stem cells were successfully collected in 24 of 27 (89%) patients who completed the first two phases of therapy, and 20 patients received an ASCT.

After a median follow-up of 4 years, 17 of the 38 patients (45%) on study were still relapse free following treatment. The 2-year event-free survival was 50%.

Today, 16 patients from the study are still alive, for a 5-year overall survival rate of 41%. The 5-year overall survival rate for patients who went on to receive transplant was 68%.

Adverse events were generally manageable with grade 4 febrile neutropenia in 3% of patients and grade 4 non-hematologic toxicity in 2% of patients. Those 60 and older did not have many more acute adverse events compared with their younger counterparts. Four patients died on study due to toxicity.

The trial demonstrated that patients over age 65 with a poor performance status had the same survival probability as younger, more fit patients. According to the study authors, the intensive regimen is appropriate for patients between 18 and 70 years of age and should be a standard therapeutic option for B-cell lymphoma patients with secondary CNS disease.

The current study, along with a previously published phase II trial from Germany, “demonstrate that significant progress has been made toward cure in this difficult population of patients,” wrote Norbert Schmitz, MD, PhD, and Huei Shan Wu, both of the Asklepios Hospital St Georg, in Hamburg, Germany, in an accompanying editorial, “a condition that was almost unanimously fatal only a few years ago.”