Beta-2 microglobulin as a prognostic factor of primary central nervous system lymphoma

TO THE EDITOR: Primary central nervous system lymphoma (PCNSL) is an extra-nodal non-Hodgkin lymphoma involving the brain, leptomeninges, eyes, or spinal cord and no primary malignancy outside of the central nervous system (CNS). PCNSL is a rare lymphoma and accounts for only 1% of all incident lymphomas [1,2]. Prevalence of the disease is higher in the sixth to eighth decades of life. The median age at diagnosis of PCNSL is 65 years and the incidence is rising in the elderly population [3,4].

Among several previously published prognostic models, the International Extranodal Lymphoma Study Group (IELSG) and the Memorial Sloan Kettering Cancer Center (MSKCC) models are the most widely used in current practice [5,6]. Old age and poor performance status at initial diagnosis were strong poor prognostic factors commonly found in both studies. Meanwhile, serum beta-2 microglobulin (B2MG) is a well-established prognostic factor in multiple myeloma and follicular lymphoma [7,8]. Thus, the purpose of this study was to validate previously suggested prognostic factors and to evaluate prognostic value of serum B2MG level in PCNSL patients.

Methods

Patients

We retrospectively analyzed the PCNSL registry data for patients treated from March 1993 to May 2017 at the Asan Medical Center in Seoul, South Korea. Variables that were extracted from the medical records and analyzed included patient demographics, Eastern Cooperative Oncology Group (ECOG) performance status, tumor characteristics, treatment profiles, serum lactate dehydrogenase (LDH) level (normal range <250 IU/L), serum B2MG level (normal range <2.5 µg/dL), cerebrospinal fluid (CSF) total protein level, number of CNS lesions, existence of deep CNS lesions (brain stem, thalamus, basal ganglia, and cerebellum), date of disease progression, and survival status.

Statistics

Overall survival (OS) was defined as the time from the beginning of first-line therapy to death from any cause. Univariate and multivariate analyses were performed to identify prognostic factors for OS using a Cox proportional hazards model. Survival curves were estimated by the Kaplan-Meier method and compared using log-rank tests. A two-sided P-value less than 0.05 was considered statistically significant. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 21.0 (IBM Corp, Armonk, NY, USA).

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional review board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal consent was not required (IRB 2018-1275).

Results

Clinical characteristics

In total, 163 patients were identified and included in the analysis. The median follow-up duration was 3.5 years [95% confidence interval (CI), 2.4–4.6] and median OS was 4.0 years (95% CI, 2.1–5.9). Baseline patient characteristics are summarized in Table 1. The median age was 60 years (range, 19–83), 88 patients (54.0%) were 60 years of age or older and 89 patients (54.6%) were males. All patients received high-dose methotrexate-based chemotherapy as initial treatment. Human immunodeficiency virus (HIV) serology was checked in 67 patients at the time of diagnosis and all were negative.

Table 1. Baseline clinical characteristics.

^a)Not confirmed in histology means lymphoid malignancy without established exact diagnosis among NHL subtypes.

Abbreviations: ASCT, autologous stem cell treatment; CNS, central nervous system; CR, complete response; CSF, cerebrospinal fluid; DLBCL, diffuse large B-cell lymphoma; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; PD, progressive disease; PR, partial response; SD, stable disease.

Prognostic factors

Univariate analysis of prognostic factors revealed that poor performance status [Eastern Cooperative Oncology Group Performance scale (ECOG PS) ≥2] and elevated serum B2MG (≥1.8 µg/mL) were significantly associated with shorter OS (Table 2). Old age (≥60 yr) showed borderline association in terms of poor OS [hazard ratio (HR) 1.55; 95% CI, 0.95–2.52; P=0.068]. Multivariate analysis results were consistent with HRs of 2.5 (95% CI, 1.06–3.03; P=0.001) for ECOG PS ≥2 and 1.79 (1.06–3.03; P=0.038) for elevated serum B2MG (≥1.8 µg/mL). The survival curves of the two groups according to serum B2MG level are shown on Fig. 1.

Table 2. Univariate analysis and multivariate analysis of overall survival.

Abbreviations: CI, confidence interval; CNS, central nervous system; CSF, cerebrospinal fluid; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; LDH, lactate dehydrogenase; OS, overall survival; PFS, progression-free survival.

Fig. 1. Overall survival from the initiation of first-line treatment.

Discussion

In our analysis, ECOG PS higher than 1 and elevated serum B2MG level were significantly predictive of poor prognosis according to univariate analysis. Most studies defined a cutoff level of serum B2MG level between 2.0 to 3.5 and our analysis showed 1.8 as the best cutoff level to establish a significant survival benefit [7,8,9]. Although the mechanism underlying the negative prognostic impact of elevated serum B2MG is unclear, a widely accepted hypothesis is that it is related to high tumor burden [9,10]. Based on this hypothesis, we might explain the relatively low cutoff level of B2MG in PCNSL by reiterating that even a small elevation of serum B2MG could reflect high tumor burden in the CNS. Our results are reliable considering the large number of enrolled patients and comparable survival outcomes of our cohort with other studies [6]. In the MSKCC study, 240 patients were enrolled, and the median OS and failure-free survival were 37 (95% CI, 31–42) months and 17 (95% CI, 12–21) months, respectively.

Our study has some limitations including the retrospective nature and also it is a single center study. Another limitation is that the cut-off value of B2MG level 1.8 µg/dL is arbitrary. However, the cutoff value in this study represents only a population from single center. Higher serum B2MG level could have some relationship with survival outcomes in PCNSL and further investigations via multi-center studies are needed. In conclusion, ECOG performance status and serum B2MG were associated with prognosis in PCNSL patients. Serum B2MG may have some association with prognosis of PCNSL.