R-MPV followed by high-dose chemotherapy with TBC and autologous stem-cell transplant for newly diagnosed primary CNS lymphoma

Abstract

• We conducted a phase-2 study in newly diagnosed PCNSL utilizing R-MPV and HDC with ASCT.• Excellent disease control and OS (2-year PFS: 79%) were observed, with an acceptable toxicity profile and minimal neurotoxicity.High-dose methotrexate-based chemotherapy is the mainstay of treatment of primary central nervous system lymphoma (PCNSL), but relapses remain frequent. High-dose chemotherapy (HDC) with autologous stem-cell transplant (ASCT) may provide an alternative to address chemoresistance and overcome the blood-brain barrier. In this single-center phase-2 study, newly diagnosed PCNSL patients received 5 to 7 cycles of chemotherapy with rituximab, methotrexate (3.5 g/m 2 ), procarbazine, and vincristine (R-MPV). Those with a complete or partial response proceeded with consolidation HDC with thiotepa, cyclophosphamide, and busulfan, followed by ASCT and no radiotherapy. Primary end point was 1-year progression-free survival (PFS), N 5 32. Median age was 57, and median Karnofsky performance status 80. Following R-MPV, objective response rate was 97%, and 26 (81%) patients proceeded with HDC-ASCT. Among all patients, median PFS and overall survival (OS) were not reached (median follow-up: 45 months). Two-year PFS was 79% (95% confidence interval [CI], 58-90), with no events observed beyond 2 years. Two-year OS was 81% (95% CI, 63-91). In transplanted patients, 2-year PFS and OS were 81%. There were 3 treatment-related deaths. Prospective neuropsychological evaluations suggested relatively stable cognitive functions posttransplant. In conclusion, this treatment was associated with excellent disease control and survival, an acceptable toxicity profile, and no evidence of neurotoxicity thus far. This trial was registered at www.clinicaltrials.gov as NCT00596154. (Blood. 2015;125(9):1403-1410 IntroductionMore than 90% of patients with primary central nervous system lymphoma (PCNSL) display a diffuse large B-cell lymphoma (DLBCL) phenotypic subtype, but standard DLBCL regimens such as cyclophosphamide, doxorubicin, vincristine and prednisone and variations are ineffective in this disease.1,2 This has been explained by poor penetration of these agents across the blood-brain barrier (BBB), a problem that has been partially addressed with the development of high-dose methotrexate-based regimens (HD-MTX) that result in therapeutic central nervous system (CNS) and cerebrospinal fluid (CSF) levels after rapid infusions of 1.5 to 8 g/m 2 . 3-5 Such high methotrexate doses are made possible with the concomitant use of leucovorin, which prevents bone marrow and systemic organ damage, while limiting rescue of lymphoma cells in the CNS because it has poor BBB penetration. This clever strategy, used with or without wholebrain radiotherapy (WBRT), has resulted in remarkable survival improvements, with recent studies reporting median overall survival (OS) of 31 to 79 months, 6-13 as compared with 12 months observed with WBRT alone.14 In spite of these improvements, early and late relapses remain frequent, and the majority of pa...

A single institutional retrospective evaluation for younger patients with primary central nervous lymphomas on a modified R-MPV regimen followed by radiotherapy and high dose cytarabine

“…29 Antonio Omuro et al previously conducted a single center phase 2 study in newly diagnosed PCNSL utilizing the R-MPV induction therapy and HD-AC, followed by consolidation HDC-ASCT with thiotepa, busulfan, and cyclophosphamide (TBC). 30 In their series, excellent disease-free control and OS (3-year OS, 81%; PFS, 79%) were observed, with an acceptable toxicity profile and minimal neurotoxicity. 30 Interestingly, a small phase 2 study suggested that HDC-ASCT could replace consolidation radiotherapy, with a 3-year OS of 77%.…”

A diffúz nagy B-sejtes lymphoma modern szemlélete és kezelése

“…Ha kellő tapasztalat és gyakorlat rendelkezésre áll, akkor lehet R-CHOP14-protokollt is alkalmazni, amelyből 6 ciklus is elegendő, de javasolt a +2 ciklus rituximab alkalmazása. Amennyiben a kiindulási betegség bulky jellegű volt, akkor javasolt a kemoterápia végén a kiindulási bulky terület involved field (IF) irradiációja csökkentett dózissal (30)(31)(32)(33)(34)(35)(36). Az agresszív, nagy rizikójú csoportba tartozó (IPI) betegek esetén az első vonalbeli kemoterápia után indokolt lehet az autológ csontvelő-transzplantáció elvégzése is, mivel egy viszonylag új tanulmány alapján a 2 éves OS transzplantá-cióval 82%, míg transzplantáció nélkül csak 64% [30].…”

“…Az R-MPV (rituximab, metorexát, procarbazin, vincristin) 2 hetente alkalmazva, majd fiatalabb betegeken a Thiotepa-Busulfan-Cytoxan kondicionálással autológ őssejttranszplantáció nagyon biztató eredményeket mutat, mivel 2 évnél az OS 80% és platót képez [33]. A rituximab nagy dózisú (3,5 g/m 2 ) metotrexát adásával még egészen idős, akár 90 éves betegekben is biztonsággal alkalmazható.…”

Immunohistochemical profile and prognostic significance in primary central nervous system lymphoma: Analysis of 89 cases

“…Morphologically, ~95% of these tumors are diffuse large B cell lymphoma (DLBCL), according to the new World Health Organization classification (5). Although the prognosis of PCNSL has been improved by optimal systemic treatment based on high-dose methotrexate (HD-MTX) (6)(7)(8), the overall survival (OS) of the majority of patients remains poor. This underlines the need to identify prognostic biomarkers for potential therapeutic targets and risk-stratified treatment.…”