Relapse of diffuse large B cell lymphoma (DLBCL) in the central nervous system (CNS) is a devastating event with dismal prognosis. Several risk factors for CNS recurrence have been reported including parameters of the International Prognostic Index (IPI) and involvement of particular extranodal sites by lymphoma. These have been combined into a risk stratification tool termed CNS-IPI (Schmitz et al, JCO 2016). The method and efficacy of CNS prophylaxis remain controversial.
We analyzed a large single institution cohort of patients with DLBCL treated in the rituximab era and who were candidates to receive intrathecal (i.t.) prophylaxis with methotrexate according to the guidelines of the Italian Society of Hematology (SIE) of 2006. We analyzed risk factors for CNS recurrence and the possible impact of i.t. prophylaxis on CNS recurrence.
From our patient registry, we identified 684 patients with diffuse large B cell lymphoma diagnosed between 1/2006 and 12/2017. Ten patients (1.5%) with CNS involvement at diagnosis were excluded. Fifty-six patients (8.3%) aged >80 years were not considered candidates for i.t. CNS prophylaxis. In the final analysis, we included 618 patients who were potential candidates for i.t. prophylaxis when risk factors, according to the SIE guidelines, were present. Prophylaxis consisted in 4 cycles of i.t. methotrexate during the first 4 cycles R-CHOP and was administered to 177 patients (29%). We investigated the incidence of CNS relapse according to CNS-IPI, involvement of particular extranodal sites and application of i.t. prophylaxis in a competing-risk analysis with systemic relapses as competing event.
Progression-free survival at 4 years in 618 patients with DLBCL was 72% (95% C.I., 67–75%). We observed 159 events of disease recurrence, of these 16 involved the CNS. CNS relapse involved the brain parenchyma in 10 patients and leptomeningeal infiltration occurred in 6 patients. CNS relapses were observed in 5/227 patients with a CNS-IPI score 0–1, in 4/286 patients with a CNS-IPi score 2–3 and in 7/149 patients with CNS-IPI score ≥4. Considering systemic relapse as competing risk, a CNS-IPI score ≥4 was only of borderline significance (p = 0.08). Analyzing for involvement of extranodal sites we found that involvement of testes, peripheral blood and kidney/adrenal glands (the latter sites combined with > 3-fold elevation of LDH) were associated with high risk of CNS relapse (>20%). As these risk factors were independent, they could be combined into a risk model. Patients with at least one risk factor had a 15.6-fold (95% C.I, 5.1–48.3) risk of CNS recurrence. This risk was not modified by administration of intrathecal prophylaxis.
Involvement of extranodal sites as testes and peripheral blood that are not included in the CNS-IPI, in addition to kidney/adrenal glands should be considered high-risk factors for CNS recurrence. Prophylaxis with i.t. methotrexate appears not to be sufficient to contrast this risk.