High-dose chemotherapy plus autologous stem cell transplant shows promise for CNS lymphoma

High-dose chemotherapy with autologous stem cell transplantation demonstrated efficacy for younger patients with newly diagnosed primary central nervous system lymphoma, according to the results of a prospective trial.

“High-dose methotrexate combined with high-dose cytarabine followed by consolidating whole-brain radiotherapy is currently regarded as standard treatment,” Gerald Illerhaus, MD, director of the clinic for hematology and oncology at Klinikum Stuttgart in Stuttgart, Germany, and colleagues wrote. “High-dose chemotherapy with autologous stem cell transplantation (HCT-ACST) is more resource demanding than whole-brain radiotherapy, but is a very promising approach as consolidation therapy. The rationale behind use of HCT-ASCT in primary CNS lymphoma treatment includes administration of maximum tolerable doses of cytostatic drugs to overcome drug resistance and reaching of therapeutic concentrations in chemotherapy sanctuaries like the CNS compartment.”

Illerhaus and colleagues hypothesized that HCT-ASCT could overcome the blood–brain barrier and eliminate residual disease. Further, replacing whole-brain radiotherapy with HCT-ASCT could reduce the risk for long-term neurotoxic adverse events.

Researchers evaluated the efficacy HCT-ASCT following high-dose chemotherapy in 79 patients (median age, 56 years; range, 51-62) with newly diagnosed CNS lymphoma who were enrolled between January 18, 2007 and May 23, 2011.

High-dose induction therapy consisted of five courses of 375 mg/m² IV rituximab (Rituxan; Genentech, Biogen) and four courses of 8,000 mg/m² IV methotrexate followed by two courses of IV rituximab (375 mg/m² on day 1), cytarabine (400 mg/m² on days 2 and 3) and thiotepa (40 mg/m² on day 3).

During induction therapy, 21 patients achieved a complete response and 52 achieved a partial response. These 73 patients went on to receive HCT-ASCT, which consisted of IV rituximab (375 mg/kg on day 1), carmustine (400 mg/m² on day 2) and thiotepa (2x5 mg/kg on days 3 and 4).

The primary endpoint was a complete response 30 days after HCT-ASCT. Safety served as a secondary endpoint.

At 30-day follow-up, 61 patients (77.2%; 95% CI, 66.1-86.6) achieved complete response and 11 patients (13.9%; 95% CI, 7.5-24) achieved partial response.

Ten patients who did not achieve complete response at 30-day follow-up received 45 Gy of whole-brain radiotherapy, half of whom demonstrated a complete radiographic response on the first scan following therapy.

Common grade 4 toxicities during induction therapy included thrombocytopenia (63%) and leucopenia (47%). The most common toxicities among patients who received HCT-ASCT included grade 4 thrombocytopenia (92%) or leucopenia (93%, as well as grade 3 anemia (53%), infection (55%) and fever (68%).

Five patients died of treatment-related adverse events, four of which occurred during induction and one 4 weeks after HCT-ASCT.

Researchers acknowledged that the single-arm study design does not allow researchers to compare the efficacy of HCT-ASCT with other consolidation approaches, such as whole-brain radiotherapy.

“For newly diagnosed primary CNS lymphoma, sequential rituximab and high-dose methotrexate and rituximab, cytarabine and thiotepa induction treatment followed by HCT-ASCT with thiotepa carmustine leads to very high remission, while associated toxicity is well manageable,” Illerhaus and colleagues wrote.

These data could be an important first step toward more efficient therapies, Stefan Hohaus, MD, aggregate professor of hematology at Istituto di Ematologia, Universita Cattolica del Sacro Cuore, in Rome, wrote in an accompanying editorial.

“One of the most discussed topics is whether whole-brain radiotherapy could be replaced by consolidations with high-dose therapy followed by autologous stem cell transplantation, which would increase disease control and reduce neurotoxicity,” he wrote. “Identification of potential molecular targets in primary CNS lymphoma as the frequent presence of mutations in the MyD88 gene raises the hope that biological agents will add further therapeutic options in the near future for this disease.” – by Nick Andrews

Disclosure: Amgen provided financial support for this research. Illerhaus reports personal fees from Amgen and Riemser. Please see the full study for a list of all other researchers' relevant financial disclosures. Hohaus reports no relevant financial disclosures.