First-line induction chemotherapy with high-dose methotrexate versus teniposide in patients with newly diagnosed primary central nervous system lymphoma: a retrospective, multicenter cohort study

This was a retrospective multicenter study of immunocompetent adults with newly diagnosed PCNSL at 22 centers in China from 2007 to 2016. The inclusion criteria were as follows: patients ≥ 18 years older; immunocompetent patients; patients with newly diagnosed PCNSL confirmed by histology or cytology from cerebrospinal fluid (CSF); patients with no previous cytotoxic treatment; patients with no evidence of extra-CNS involvement; patients receiving either high-dose methotrexate (HD-MTX) (MTX cohort: high-dose methotrexate-based regimen treatment, 3–3.5 g/m² methotrexate daily on day 1 every 14 days, with or without rituximab 375 mg/m² on day 0) or teniposide (TEN cohort: teniposide-based regimen treatment, 60 mg/m² teniposide daily on days 1–5 every 21 days, with or without rituximab 375 mg/m² on day 0) as the first-line induction therapy. The major exclusion criteria were concomitant immunosuppression, including positive human immunodeficiency virus serology; no assessment of chemotherapy, and no long-term survival result. All clinical management decisions and response evaluations were independently performed by the patients’ treating physicians. The study was approved by the local institutional ethic committee. As our study involved only a retrospective review of previous clinical data, the requirement for informed consent was waived.

The demographic data and clinical features of all patients were obtained retrospectively from the medical records. The clinical variables included age at diagnosis, sex, ethnicity, height, weight, body surface area, Eastern Cooperative Oncology Group (ECOG) performance score, year of diagnosis, symptoms at diagnosis, presence/absence of B symptoms, result of pathology, International Extranodal Lymphoma Study Group (IELSG) score of primary CNS lymphoma, lactate dehydrogenase (LDH), protein level of CSF, sites of intracranial lesions, comorbidities (hypertension, coronary disease, diabetes, hyperlipidemia, viral hepatitis B, etc.), induction regimen and its toxicity, inclusion of rituximab, number of cycles, response (complete response, CR; partial response, PR; stable disease, SD; progressive disease, PD), use/type/timing of stem cell transplantation, use of radiotherapy, progression-free survival (PFS), OS, and cause of death.

The purpose of this study was to compare the efficacy and safety of a teniposide-based regimen with a high-dose methotrexate-based regimen in patients with newly diagnosed primary CNS lymphoma. The outcomes were objective response rate [including complete response rate and overall response rate (ORR) after induction chemo/immunotherapy], PFS, and OS. The OS was calculated from the time of diagnosis to death of any cause or, for the patients alive, to the date of the last follow-up, whereas PFS was the time from diagnosis to the time of relapse or progression or death from any cause. The International PCNSL Collaborative Group Response Criteria [21] was used for response assessment. Our study also analyzed the toxicity of patients in these 2 cohorts 1 month after chemotherapy. The toxicities of MTX and TEN cohorts were assessed with the Common Terminology Criteria for Adverse Events version 4.0.

The baseline (pretreatment) and treatment variables were collected, along with dates of first progression, last follow-up, and death. The normally distributed variables were expressed as mean ± standard deviation (SD), and the skewed or unknown distributed variables were displayed as the median and interquartile range (IQR). The categorical variables were presented as count (percentage). The univariate analyses (UVA) for OS were performed using each of the pretreatment variables evaluated. The survival analyses were performed regardless of the duration or type of therapy received. PFS and OS rates were estimated using the Kaplan–Meier method, and differences were assessed with the log-rank (Mantel–Cox) test. Variables with a P value < 0.05 on UVA were included in the stepwise multivariate Cox proportional-hazards model. Hazard ratios (HRs) and their 95% confidence intervals (CIs) were calculated. The Cox proportional-hazards model was recalculated with the addition of an induction regimen as a variable to evaluate the impact of the induction regimen. Kaplan–Meier survival curves were generated. Analyses were done with IBM SPSS software (version 20·0). The differences in categorical data were calculated using the chi-square or Fisher’s exact test with significance defined as P ≤ 0.05. All P values were two tailed.

Full survival data were available for 96 eligible patients from 22 centers in China. Of these, 62 patients received treatment with MTX monotherapy with or without rituximab (MTX cohort), and 34 patients received teniposide monotherapy with or without rituximab (TEN cohort). The proportion of patients whose tissue samples were obtained by stereotactic biopsy in the MTX cohort was significantly lower than that in the TEN cohort (29.5% vs 50.0%,), while the proportion of patients whose tissue samples were obtained by surgical partial resection was significantly higher than that in the TEN cohort (70.5% vs 50.0%) (P = 0.047). No significant differences were found in age, sex, ECOG performance status, IELSG risk, LDH level, CSF cytology, lymphoma categories, comorbidities, and the combination of MTX/TEN with rituximab and radiotherapy between the 2 cohorts (Table 1). The median age of the whole cohort was 55 years (range, 22–74 years), with 51.5 years in the TEN cohort (range, 22–74 years) and 58 years in the MTX cohort (range, 23–74 years) (P = 0.655). The ratio was 1.13:1 in all patients, with no difference between the two cohorts. Nearly half of the patients had poor performance status (ECOG PS ≥ 2). More than 95% patients in both cohorts had B-cell lymphoma, and most of them had diffuse large B-cell lymphoma. Most patients were diagnosed by stereotactic or surgical biopsy, and only one patient in the MTX cohort was diagnosed by cytology from CSF. The comorbidities in two groups were similar, including hypertension, coronary disease, diabetes, hyperlipidemia, viral hepatitis B. In MTX group, there was one patient with depressive state, one patient cured gastric cancer, and one patient with hysterectomy. In TEN group, there was 1 patient with a mass on kidney without pathological diagnosis and 1 patient with hysterectomy. Less than half of the patients in both cohorts received MTX or teniposide with rituximab as the first-line induction therapy, and nearly half of the patients received radiotherapy as a consolidation therapy after MTX or teniposide.

The response rate was 90.3% in the MTX cohort and 97.1% in the TEN cohort. The median follow-up duration was 44 months (range, 1–81 months) in the MTX cohort and 39 months (range, 2–61 months) in the TEN cohort. The ORR was 73.2% and 72.7% in the MTX and TEN cohorts (P = 0.627). The complete response rate in the MTX cohort was higher than that in the TEN cohort, with no statistically significant difference (P = 0.182). According to the IELSG score, no difference in overall responses was found among three levels (P = 0.467). Four patients in the MTX cohort and 1 patient in the TEN cohort received autologous hematopoietic stem cell transplantation (ASCT) after the methotrexate and teniposide induction therapy. It might partially explain the higher complete response rate in the MTX cohort. None of the enrolled patients underwent allogeneic hematopoietic stem cell transplantation. Of all 89 patients who received at least 1 dose of first-line chemotherapy and fulfilled all eligibility criteria, 2 (3.6%) died during first-line therapy in the MTX cohort. The causes of death were cerebral bleeding (n = 1, 1.8%) and acute toxic effect (n = 1, 1.8%) (Table 2).

During follow-up, the median PFS was 28.4 months (95% CI: 13.7–51.2) in the MTX cohort and 24.3 months (95% CI: 16.6–32.1) in the TEN cohort (P = 0.75; Fig. 1A), with a 3-year PFS of 48.7% and 34.1%. The median OS was 31 months (95% CI: 26.8–35.2) in the MTX cohort and 32 months (95% CI: 27.6–36.4) in the TEN cohort (P = 0.77; Fig. 1B), with a 3-year OS of 41.9% and 41.7%, respectively. A total of 42 events were reported in the MTX cohort (relapse after responsive or stable disease in 25 patients, death while relapse-free in 2 patients, death while early progressive disease in 2 patients, death due to tumor progression in 12 patients, and death for unknown reason in 1 patient), and 33 events in the TEN cohort (relapse after responsive or stable disease in 17 patients, death while relapse-free in 2 patients, death while early progressive disease in 1 patient, death due to tumor in 13 patients, and death for unknown reason in 1 patient).

The univariate and multivariate analyses found that age, ECOG, rituximab, and radiotherapy were not significantly associated with OS. However, the IELSG risk was significantly associated with a worse OS in univariate and multivariate analyses (low vs intermediate, P = 0.003; low vs high, P = 0.002) (Table 3).

Table 4 summarizes all hematological and non-hematological toxic effects that occurred during first-line chemotherapy. The prevalence of hematological toxic effects in the two cohorts was similar. The coagulopathy or DVT was more common in the MTX cohort: 13.5% with grade 1 and 1.9% with grade 5 in the MTX cohort versus 0 in the TEN cohort. The gastrointestinal toxic effects increased in the TEN cohort, but all were of grade 1–2. Acute neurotoxicity was reported in two patients (1 grade 4 and 1 grade 5, 3.8%) in the MTX cohort compared with one patient (grade 1–2, 3%) in the TEN cohort (P = 0.832).

The most common adverse reactions during treatment in patients in the MTX and TEN cohorts included neutropenia, thrombocytopenia, anemia, febrile neutropenia/infections, hepatotoxicity, nephrotoxicity, coagulopathy/DVT, gastrointestinal, mucositis, and acute neurotoxicity. In the MTX cohort, common grade 4 adverse events included neutropenia (19.2%), thrombocytopenia (13.5%), anemia (19.2%), febrile neutropenia/infections (1.9%), mucositis (1.9%), and acute neurotoxicity (1.9%). Common grade 5 adverse events included febrile neutropenia/infections (1.9%), coagulopathy/DVT (1.9%), and acute neurotoxicity (1.9%). In the TEN cohort, the most common grade 4 adverse events included neutropenia (24.2%), thrombocytopenia (9.1%), anemia (3%), and febrile neutropenia/infections (6.1%). Grade 5 febrile neutropenia/infections occurred in only 1 (3%) patient (Table 4).