Impact of front line relative dose intensity for methotrexate and comorbidities in immunocompetent elderly patients with primary central nervous system lymphoma

Abstract

Primary central nervous system lymphomas (PCNSL) are non-Hodgkin lymphomas strictly localized to the CNS, occurring mainly in elderly patients with comorbidities. Current treatment in fit patients relies on high-dose methotrexate and high-dose cytarabine. The aim of this study was to evaluate the efficacy and feasibility of this treatment in elderly patients and to assess potential prognostic factors associated with survival. We conducted a retrospective study in two centers between January 2008 and September 2015 including 35 elderly immunocompetent patients who received first-line treatment with high-dose methotrexate. With a median follow-up of 19.8 months (range: 1.7-73.4 months), median overall survival (OS) was 39.5 months (95% confidence interval (95% CI): 18.3-60.7) and median progression-free survival (PFS) was 25.8 months (95% CI: 5.2-46.4). In univariate analysis, administration of high-dose cytarabine and achieving a relative dose intensity for methotrexate > 75% were associated with increased OS (p = 0.006 and p = 0.003, respectively) and PFS (p = 0.003 and p = 0.04, respectively) whereas comorbidities, defined by a CIRS-G score ≥ 8, were associated with decreased OS and PFS (p = 0.02 and p = 0.04, respectively). A high MSKCC score was associated with decreased OS (p = 0.02). In multivariate analysis, administration of high-dose cytarabine was associated with increased OS and PFS (p = 0.02 and p = 0.007, respectively). Comorbidities and relative dose intensity for methotrexate are important for the prognosis of elderly patients with PCNSL. These results must be confirmed in prospective trials.

Outcomes of older patients with primary central nervous system lymphoma treated in routine clinical practice in the UK: methotrexate dose intensity correlates with response and survival

“…Survival outcomes for older patients remain poor and have been the focus of several recent trials. [10][11]13,16 Outcomes of the less intensive group in our study (two-year PFS 11%) were inferior to those of recent retrospective studies, one of patients >60 years (two-year PFS of 52%) 16 and another with a subgroup analysis of patient >60 years (median PFS of 39 months). 17 These study populations had a better ECOG and a younger age than our less intensive cohort, potentially explaining this finding.…”

“…Data from the HOVON105/ALLG NHL 24 prospective trial did not demonstrate benefit of rituximab in terms of event‐free survival (EFS) when added to the MBVP induction regimen (one‐year EFS 52% vs. 49%) 22 although a study level meta‐analysis of pooled data from IELSG32 and HOVON105 confirmed a PFS benefit 23 . Notwithstanding, most centres now routinely include rituximab within PCNSL protocols and our study supports this approach 5,16‐17,24,25 …”

“…23 Notwithstanding, most centres now routinely include rituximab within PCNSL protocols and our study supports this approach. 5,[16][17]24,25 The proportion of patients receiving palliative care in our cohort (21%) is higher compared to published single-centre series of patients >65 years (13% receiving active palliation including radiotherapy). 26 Novel therapies are urgently needed for this group of patients.…”

“…Although the optimal cumulative dose of MTX remains controversial (varying from 14 g/m 2 in the ILESG32 trial 5 to 64 g/m 2 in the rituximab, methotrexate and temozolomide (R-MT) regimen 7 ), our data are in line with previous work identifying MTX dose as a factor associated with survival in older patients. 10,16 Patients receiving a MTX-RDI <0Á75 had significantly worse outcomes, and hence, MTX dose reductions below this threshold should be carefully considered, based on our data.…”

Treatment Regimens for Immunocompetent Elderly Patients with Primary Central Nervous System Lymphoma: A Scoping Review

“…In total we identified five completed [32,42,43,45,49,50] and one ongoing RCT [29], 26 prospective studies (two with control [67,69], 24 single arm studies [31,[55][56][57][58][59][60][61][62][63][64][65][66]68,[70][71][72][73][74][75][76][77][78][79] and 24 retrospective studies (with or without control) [17,30,37,45,[80][81][82][83][84][85][86][87][88][89][90][91][92]…”