A prospective observational study of real-world treatment and outcome in secondary CNS lymphoma

BACKGROUND: Secondary central nervous system lymphoma (SCNSL) confers a dismal prognosis and treatment advances are constrained by the lack of prospective studies and real-world treatment evidence. METHODS: Patients with SCNSL of all entities were included at first diagnosis and patient characteristics, treatment data, and outcomes were prospectively collected in the Secondary CNS Lymphoma Registry (SCNSL-R) (NCT05114330). FINDINGS: 279 patients from 47 institutions were enrolled from 2011 to 2022 and 243 patients (median age: 66 years; range: 23-86) were available for analysis. Of those, 49 (20 %) patients presented with synchronous (cohort I) and 194 (80 %) with metachronous SCNSL (cohort II). The predominant histology was diffuse large B-cell lymphoma (DLBCL, 68 %). Median overall survival (OS) from diagnosis of CNS involvement was 17·2 months (95 % CI 12-27·5), with longer OS in cohort I (60·6 months, 95 % CI 45·5-not estimable (NE)) than cohort II (11·4 months, 95 % CI 7·8-17·7, log-rank test p < 0.0001). Predominant induction regimens included R-CHOP/high-dose MTX (cohort I) and high-dose MTX/cytarabine (cohort II). Rituximab was used in 166 (68 %) of B-cell lymphoma. Undergoing consolidating high-dose therapy and autologous hematopoietic stem cell transplantation (HDT-ASCT) in partial response (PR) or better was associated with longer OS (HR adjusted 0·47 (95 % CI 0·25-0·89), p = 0·0197). INTERPRETATION: This study is the largest prospective cohort of SCNSL patients providing a comprehensive overview of an international real-world treatment landscape and outcomes. Prognosis was better in patients with SCNSL involvement at initial diagnosis (cohort I) and consolidating HDT-ASCT was associated with favorable outcome in patients with PR or better

Getting TRAIL back on track for cancer therapy

Unlike other members of the TNF superfamily, the TNF-related apoptosis-inducing ligand (TRAIL, also known as Apo2L) possesses the unique capacity to induce apoptosis selectively in cancer cells in vitro and in vivo. This exciting discovery provided the basis for the development of TRAIL-receptor agonists (TRAs), which have demonstrated robust anticancer activity in a number of preclinical studies. Subsequently initiated clinical trials testing TRAs demonstrated, on the one hand, broad tolerability but revealed, on the other, that therapeutic benefit was rather limited. Several factors that are likely to account for TRAs' sobering clinical performance have since been identified. First, because of initial concerns over potential hepatotoxicity, TRAs with relatively weak agonistic activity were selected to enter clinical trials. Second, although TRAIL can induce apoptosis in several cancer cell lines, it has now emerged that many others, and importantly, most primary cancer cells are resistant to TRAIL monotherapy. Third, so far patients enrolled in TRA-employing clinical trials were not selected for likelihood of benefitting from a TRA-comprising therapy on the basis of a valid(ated) biomarker. This review summarizes and discusses the results achieved so far in TRA-employing clinical trials in the light of these three shortcomings. By integrating recent insight on apoptotic and non-apoptotic TRAIL signaling in cancer cells, we propose approaches to introduce novel, revised TRAIL-based therapeutic concepts into the cancer clinic. These include (i) the use of recently developed highly active TRAs, (ii) the addition of efficient, but cancer-cell-selective TRAIL-sensitizing agents to overcome TRAIL resistance and (iii) employing proteomic profiling to uncover resistance mechanisms. We envisage that this shall enable the design of effective TRA-comprising therapeutic concepts for individual cancer patients in the future.Cell Death and Differentiation advance online publication, 20 June 2014; doi:10.1038/cdd.2014.81