Phase II Trial of High-Dose Rituximab with Thiotepa / Busulfan / Cyclophosphamide (TBC) Autologous Stem Cell Transplantation for Patients with CNS Involvement by Non-Hodgkin Lymphoma

High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) has recently been shown to be safe and effective in patients with central nervous system (CNS) involvement by NHL.  Rituximab (R) has been incorporated into the therapy for CNS NHL, although there is limited penetration of R across the intact blood brain barrier and into the cerebrospinal fluid (CSF).  23 patients were treated on a phase II study using high-dose rituximab in combination with high-dose cytarabine for autologous stem cell mobilization followed by HDT with thiotepa, busulfan, and cyclophosphamide (TBC), followed by ASCT.  Median age was 58 (range 24-73).  All patients received 2 doses of R at 1000 mg/m2/dose on days 1 and 8 of high-dose cytarabine mobilization chemotherapy and 2 doses on days -9 and -2 of TBC.  12 patients had primary CNS NHL (7 CR1, 5 relapsed) and 11 patients had secondary CNS involvement from systemic NHL. All patients were in a chemosensitive partial or complete remission before mobilization therapy.  All patients tolerated infusions of high dose R without reactions. All patients achieved neutrophil engraftment (median 9 days, range 8-12) and platelet engraftment (median 12 days, range 8-40). The most common toxicities were diarrhea and mucositis.  Two patients developed significant neurotoxicity, one who had previously had whole brain radiation therapy and another who was thought to develop thrombotic microangiopathy in the setting of candidemia.  The 100-day transplant-related mortality rate was 0% and one patient died 5 months after ASCT due to neurological complications without evidence of lymphoma.  At a median follow-up of 399 days (range 54-705 days), only one patient, who had multiply relapsed cutaneous and CNS large cell lymphoma, had relapsed disease, and only one patient has died.  Three patients had optional lumbar punctures performed 24-36 hours after the first dose of high-dose R to determine CSF levels of R.  In those patients, R was present in the lumbar CSF at concentrations of 343-498 ng/ml. CSF rituximab levels were about 0.1% of simultaneously obtained serum concentrations. For patients with CNS involvement by NHL, a regimen of high-dose R with high-dose cytarabine for stem cell mobilization followed by high-dose R with TBC autologous stem cell transplantation is feasible.  Concentrations of R measured in the CSF are about 0.1% of that achieved in the peripheral blood, demonstrating limited penetration past the blood-brain-barrier.  High-dose rituximab in combination with TBC followed by ASCT shows encouraging clinical activity and merits further study in patients with CNS NHL.