RESUMO
Myelodysplastic syndromes/neoplasms (MDS) are clonal hematologic disorders characterized by morphologic abnormalities of myeloid cells and peripheral cytopenias. While genetic abnormalities underlie the pathogenesis of these disorders and their heterogeneity, current classifications of MDS rely predominantly on morphology. We performed genomic profiling of 3,233 patients with MDS or related disorders to delineate molecular subtypes and define their clinical implications. Gene mutations, copy-number alterations (CNAs), and copy-neutral loss of heterozygosity (cnLOH) were derived from targeted sequencing of a 152-gene panel, with abnormalities identified in 91, 43, and 11% of patients, respectively. We characterized 16 molecular groups, encompassing 86% of patients, using information from 21 genes, 6 cytogenetic events, and LOH at the TP53 and TET2 loci. Two residual groups defined by negative findings (molecularly not-otherwise specified, absence of recurrent drivers) comprised 14% of patients. The groups varied in size from 0.5% to 14% of patients and were associated with distinct clinical phenotypes and outcomes. The median bone marrow blast percentage across groups ranged from 1.5 to 10%, and the median overall survival from 0.9 to 8.2 years. We validated 5 well-characterized entities, added further evidence to support 3 previously reported subsets, and described 8 novel groups. The prognostic influence of bone marrow blasts depended on the genetic subtypes. Within genetic subgroups, therapy-related MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) had comparable clinical and outcome profiles to primary MDS. In conclusion, genetically-derived subgroups of MDS are clinically relevant and may inform future classification schemas and translational therapeutic research.
RESUMO
Despite the improvement in overall survival in patients with diffuse large B-cell lymphoma (DLBCL) in the rituximab era, the occurrence of central nervous system (CNS) relapse heralds a very poor prognosis. The evidence is conflicting on the incidence and pattern of CNS relapse in the rituximab era compared with before the rituximab era and on the role of CNS prophylaxis. We conducted a systematic analysis of the data from 7 prospective studies, studying the incidence and type of CNS relapse, the role of prophylaxis, and survival after CNS relapse, with and without rituximab-based chemotherapy. No statistically significant difference was found in the incidence of CNS relapse with the use of rituximab-based chemotherapy compared with CHOP (cyclophosphamide, doxorubicin, vincristine [Oncovin], prednisone) chemotherapy. Leptomeningeal disease was more common and the survival after CNS disease was better in the rituximab era. No difference was found in the incidence of isolated CNS relapse. Chemoprophylaxis significantly decreased the incidence of CNS recurrence. The use of rituximab has not influenced the incidence of CNS relapse compared with the use of CHOP. Chemoprophylaxis plays a significant role in high-risk patients with DLBCL in decreasing CNS recurrence. Large randomized clinical trials are warranted to differentiate between intrathecal and systemic chemoprophylaxis.