3.1 Baseline characteristics of 123 newly diagnosed DLBCL patients.
None of the 123 newly diagnosed DLBCL patients presented CNS involvement. The clinical characteristics of 123 DLBCL patients, including 65 males and 58 females, were examined. The median age of initial DLBCL onset was 54 (41-85) years. The ECOG score was 0-2 in 96 cases (78%) and 3-4 in 27 cases (22%). Seventeen patients (13.8%) were diagnosed with DLBCL as a bulky disease. Thirty-three patients (26.8%) suffered from extranodal site involvement (excluding the CNS) at the time of onset. At onset, 57 patients (46.3%) were stage III-IV, and 66 patients (53.7%) were stage I-II. The IPI was >2 in 53 patients (43.1%) and ≤2 in the remaining 70(56.9%) patients at onset. The LDH level was higher than normal in 42 patients (34.1%). Thirty-five patients (43%) had germinal center B-cell-like (GCB) disease, fifty-two patients (30%) had non-GCB disease, and the pathological type in the remaining 36 patients was unclassified. Bone marrow involvement occurred in 17 patients (13.8%). A total of 100 patients (81.3%) were treated with rituximab and 42 patients (34.1%) were treated with dorubicin liposome.
3.2 Univariate and multivariate analysis of CNS involvement risk factors.
Of the one hundred and twenty-three cases with DLBCL, 23 patients developed CNS involvement, some due to disease progression and some due to relapse. The incidence of CNS involvement was 18.7%. All patients were analyzed as shown in the following table (Table1). Several factors were analyzed, including age, gender, ECOG score, bulky disease, extranodal site involvement, Ann Arbor stage, IPI, serum LDH, GCB or Non-GCB pathological type, bone marrow involvement, prophylactic intrathecal injection therapy, whether use rituximab and dorubicin liposome, etc. Univariate analysis showed that ECOG score＞2(P=0.006; OR=3.756), IPI＞2(P=0.005;OR=3.892), Ann Arbor stage III-IV(P=0.003; OR=4.25), Elevated serum LDH level(P=0.012;OR=3.183) were high-risk factors for DLBCL patients developing CNS involvement. Use dorubicin liposome (P=0.018; OR=0.235) was protective factor for DLBCL patients developing CNS involvement. The other factors, including age, gender, bulky disease, extranodal sites involvement, bone marrow involvement, GCB or Non-GCB pathological type and rituximab use before CNS involvement were not predictive of CNS involvement by univariate analysis. Multivariate analysis identified LDH (P=0.030; HR=4.035; 95%CI: 1.147~14.195) was as independent predictor of CNS involvement (Table 2).
3.3. Baseline characteristics, treatment, and outcome of 38 DLBCL patients with CNS involvement.
Table 3 showed that the baseline characteristics of 38 DLBCL patients with CNS involvement. From the total of 38 patients of DLBCL with CNS involvement, 15 patients had CNS involvement at initial diagnosis of DLBCL, and 23 patients were diagnosed with CNS involvement during or after first-line chemotherapy. Isolated CNS involvement occurred in 11 patients, while CNS involvement plus systemic disease occurred in 27 patients. First-line treatment for DLBCL patients with CNS involvement were different, which included high-dose methotrexate (HD-MTX) only(n=3), MTX combined CHOP(n=11), MTX combined R-CHOP(n=13), CHOP(n=4), DHAP (Dexamethasone, Cisplatin, Cytarabine) (n=2), MTX combined Idarubicin(IDA)(n=2), whole-brain radiotherapy (WBRT)(n=2), no treatment(n=1). For patients with leptomeningeal abnormal, lumbar puncture and intrathecal injection chemotherapy were given as routine treatment. In our center, we often intrathecal injection MTX，cytarabine (Ara-C) and dexamethasone(n=17). In the patients treated with HD-MTX, we used the MTX dose was 3.5-8g/m2. After 2-4 cycles of chemotherapy or one cycle of radiotherapy, 23 patients showed rapid progression. We administered second-line treatment，i.e., DHAP, ICE (Ifosfamide, Carboplatin, Etoposide), Ara-C combined with temozolomide (TMZ), and WBRT. In addition, there were four patients treated with autologous hematopoietic stem cell transplantation (ASCT).
In total, the median follow-up time was 2 years (range from 0.5 to 5.5 years). There were 15 patients (39.5%) died, 13 patients (34.2%) were in complete remission(CR), 3 patients (7.9%) were in progression disease(PD), 5 patients (13.2%) were in partial remission(PR), and 2 patients (5.2%) were in stable disease(SD). The median PFS time after-CNS involvement was 12.5 months. The median OS time after-CNS involvement was 22 months.
3.4 Analysis of prognostic factors at the time of CNS involvement.
Univariate analysis by log-rank test and multivariate analysis by cox multiple regression were performed to analyze prognostic factors among 38 patients of DLBCL with CNS involvement. Univariate prognostic analysis showed that ECOG score>2(P=0.002; HR=5.215; 95%CI:1.842~14.76), cerebrospinal fluid(CSF) protein>1.0g/L(P=0.004; HR=10.84; 95%CI:2.165~54.32), lymphocyte absolute count ≤0.75*109/L(P=0.023; HR=8.857; 95%CI:1.999~39.25) and elevated LDH level ( P=0.005; HR=5.355; 95%CI:1.648~17.4) were poor prognostic factors(Table 4). Multivariate prognostic analysis identified ECOG score>2(P=0.018; HR=7.333; 95%CI:1.424~42.002), elevated LDH level (P=0.046; HR=6.510; 95%CI:1.035~40.949), deep lesion (defined as lesions located more than 3 centimeters from the brain surface) (P=0.005; HR=10.957; 95%CI:2.050~58.569), and CNS with systemic involvement (P=0.023; HR=2.730; 95%CI:1.151~6.479) were independent poor prognostic factors. Lymphocyte absolute count ＞0.75´109/L(P=0.029; HR=0.047; 95%CI:0.003~0.732) was protective prognostic factor(Table 5). Other factors, such as gender, age≥60 years, bulky disease, CSF nuclear cells, neutrophil absolute count＜6.3´109/L, peripheral blood white blood cell(WBC) and site of CNS involvement had no impact on prognosis (P>0.05). We use these five factors (ECOG＞2, elevated LDH level, deep lesion, CNS with systemic involvement，Lymphocyte absolute count≤0.75´109/L) established a simple prognostic score system, with one point with each term, and divided into three groups of low (0-1 point)，medium (2-3 point) and high risk(4-5 point),with one year survival rate of 90.9%, 40% and 14.3% respectively.
3.5 Kaplan-Meier curve estimation of PFS and OS of DLBCL patients with and without CNS involvement.
The result revealed that the median PFS and OS durations of DLBCL patients after CNS involvement were 12.5 months and 22 months, respectively (Fig 1-2). As shown in our research, the overall survival of DLBCL patients with CNS involvement (SCNSL) was poorer than DLBCL patients without CNS involvement (P=0.032; HR=2.282; 95%CI: 1.075~4.842) (Fig 3). It is notable that there was no difference observed between the cases with CNS and extra-CNS involvement (P=0.181; HR=0.482; 95%CI: 0.165~1.405). There was no difference observed between the patients with CNS involvement at the time of DLBCL diagnosed and during or after first-line therapy (P=0.973; HR=1.182; 95%CI: 0.429~3.259). There was no significant difference between the patients with CNS involvement and stage III-IV DLBCL cases without CNS involvement (P=0.238; HR=1.555; 95%CI: 0.747~3.238) (Fig 4-6)