Phase II study of central nervous system (CNS)-directed chemotherapy including high-dose chemotherapy with autologous stem cell transplantation for CNS relapse of aggressive lymphomas

Abstract

The prognosis of patients with central nervous system relapse of aggressive lymphoma is very poor with no therapy established so far. In a prospective multicenter phase II study, we evaluated a potentially curative chemotherapy-only regimen in these patients. Adult immunocompetent patients 65 years of age or under received induction chemotherapy with MTX/IFO/DEP (methotrexate 4 g/m(2) intravenously (i.v.) Day 1, ifosfamide 2 g/m(2) i.v. Days 3- 5 and liposomal cytarabine 50 mg intrathecally (i.th) Day 6) and AraC/TT/DEP (cytarabine 3g/m(2) i.v. Days 1-2, thiotepa 40 mg/m(2) i.v. Day 2 and i.th. liposomal cytarabine 50 mg i.th. Day 3) followed by high-dose chemotherapy with carmustine 400 mg/m(2) i.v. Day -5, thiotepa 2×5 mg/kg i.v. Days -4 to -3 and etoposide 150 mg/m(2) i.v. Days -5 to -3, and autologous stem cell transplantation Day 0 (HD-ASCT). Thirty eligible patients (median age 58 years) were enrolled. After HD-ASCT (n=24), there was a complete remission in 15 (63%), partial remission in 2 (8%) and progressive disease in 7 (29%) patients. Myelotoxicity was the most adverse event with CTC grade 3/4 infections in 12% of MTX/IFO/DEP courses, 21% of AraC/TT/DEP courses and 46% of HD-ASCT courses. The 2-year time to treatment failure was 49%±19 for all patients and 58%±22 for patients completing HD-ASCT. The protocol assessed proved feasible and highly active with long-lasting remissions in a large proportion of patients. (ClinicalTrials.govIdentifier NCT01148173).

Figure 1.

Course of therapy and response. Note that one patient with progressive disease after AraC/TT/DEP received HD-ASCT. HDMTX/IFO/DEP: high-dose methotrexate, ifosfamide and liposomal cytarabine intrathecally; CR: complete response; PR: partial response; NC: no change; HDAraC/TT/DEP: high-dose cytarabine, thiotepa and liposomal cytarabine intrathecally; PD: progressive disease; HD-ASCT: high-dose chemotherapy followed by autologous stem-cell transplantation.

Figure 2.

(A) Time to treatment failure (TTF) for all patients (n=30). (B) Overall survival (OS) for all patients. (C) TTF for patients with highdose chemotherapy and autologous stem cell transplantation (HD-ASCT; n=24). (D) OS for HD-ASCT patients. For analysis B and D, time at risk started at the beginning of HD-ASCT.