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

Abstract

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 = 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.

Figure 1

PFS and OS. (A) PFS, all patients (N = 32). (B) OS, all patients (N = 32). (C) PFS and OS in transplanted patients. (D) PFS according to age (above 50 vs 50 and under). P = .05.

Figure 2

Neuropsychological testing, mood/QoL scores, and evaluation of white matter changes on MRI over time. Time points: 1, baseline; 2, after R-MPV and before transplant; 3, 4, 5, and 6, every 6 months after transplant. (A) Neuropsychological testing (z scores) boxplot. BL, baseline; BTA, Brief Test of Attention; COWA, Controlled Word Association Test; GPT-D, Grooved Pegboard Test–Dominant Hand; GPT-ND, Grooved Pegboard Test–Non-Dominant Hand; HVLT-R-DEL, Hopkins Verbal Learning Test-Revised–Delayed Recall; HVLT-R-DI, Hopkins Verbal Learning Test-Revised–Discrimination Index; HVLT-R-TL, Hopkins Verbal Learning Test-Revised–Total Learning; R-MPV, after induction chemotherapy; TMTA, Trail Making Test Part A; TMTB, Trail Making Test Part B. The z scores ≤1.5 represent impairment. The lower and upper boundaries of each box represent the first and third quartiles (ie, the 25th and 75th percentiles), respectively, at the indicated time point, and the IQR is the distance between the lower and upper boundaries. The error bars (“whiskers”) extend from the first and third quartiles to the lowest and highest scores that are within 1.5 × IQR of their respective quartile. Any scores beyond the error bars are considered outliers and are represented as individual points. The asterisks represent the median scores. The lines connecting the medians over time for each test have no statistical interpretation and are intended to serve as visual aids. (B) BDI and FACT-BR (raw scores) boxplot. See panel A for boxplot explanation. (C) White matter abnormality scores (modified Fazekas scale) over time (N = 16). Fazekas scores: 0, no white matter abnormality; 1, minimal patchy white matter foci; 2, start of confluence of white matter disease; 3, large confluent areas; 4, confluence of white matter abnormalities with cortical and subcortical involvement; 5, diffuse leukoencephalopathy. No patient developed white matter abnormality scores of 4 or 5.