Therapeutic manipulation of IKBKAP mis-splicing with a small molecule to cure familial dysautonomia.

Approximately half of genetic disease-associated mutations cause aberrant splicing. However, a widely applicable therapeutic strategy to splicing diseases is yet to be developed. Here, we analyze the mechanism whereby IKBKAP-familial dysautonomia (FD) exon 20 inclusion is specifically promoted by a small molecule splice modulator, RECTAS, even though IKBKAP-FD exon 20 has a suboptimal 5' splice site due to the IVS20 + 6 T > C mutation. Knockdown experiments reveal that exon 20 inclusion is suppressed in the absence of serine/arginine-rich splicing factor 6 (SRSF6) binding to an intronic splicing enhancer in intron 20. We show that RECTAS directly interacts with CDC-like kinases (CLKs) and enhances SRSF6 phosphorylation. Consistently, exon 20 splicing is bidirectionally manipulated by targeting cellular CLK activity with RECTAS versus CLK inhibitors. The therapeutic potential of RECTAS is validated in multiple FD disease models. Our study indicates that small synthetic molecules affecting phosphorylation state of SRSFs is available as a new therapeutic modality for mechanism-oriented precision medicine of splicing diseases

Outcomes of patients who developed subsequent solid cancer after hematopoietic cell transplantation

To characterize the outcomes of patients who developed a particular subsequent solid cancer after hematopoietic cell transplantation (HCT), age at cancer diagnosis, survival, and causes of death were compared with the respective primary cancer in the general population, using data from the national HCT registry and population-based cancer registries in Japan. Among 31 867 patients who underwent a first HCT between 1990 and 2013 and had progression-free survival at 1 year, 713 patients developed subsequent solid cancer. The median age at subsequent solid cancer diagnosis was 55 years, which was significantly younger than the 67 years for primary cancer patients in the general population (P < .001). The overall survival probability was 60% at 3 years after diagnosis of subsequent solid cancer and differed according to cancer type. Development of most solid cancers was associated with an increased risk of subsequent mortality after HCT. Subsequent solid cancers accounted for 76% of causes of death. Overall survival probabilities adjusted for age, sex, and year of diagnosis were lower in the HCT population than in the general population for colon, bone/soft tissue, and central nervous system cancers and did not differ statistically for other cancers. In conclusion, most subsequent solid cancers occurred at younger ages than primary cancers, emphasizing the need for cancer screening at younger ages. Subsequent solid cancers showed similar or worse survival compared with primary cancers. Biological and genetic differences between primary and subsequent solid cancers remain to be determined

Chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma: opportunities and challenges

B-cell non-Hodgkin lymphoma (NHL) is the most frequent hematologic malignancy. Despite the refinement of chemoimmunotherapy, a substantial number of patients experience chemorefractory disease. Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is considered the most promising and effective therapy to overcome chemorefractory B-cell NHL. Based on the promising results obtained from pivotal trials, the US Food and Drug Administration and European Medicines Agency approved anti-CD19 CAR T-cell therapy for relapsed/refractory diffuse large B-cell lymphoma. Nonetheless, there remain several controversial issues and problems awaiting solutions, including optimal management of toxicities, overcoming relapsed/refractory disease after CAR T-cell therapy, and improving CAR-T manufacturing platform. Definite unmet medical needs among patients with chemorefractory B-cell NHL still exist. CAR T-cell therapy might be a game changer that can defeat chemorefractory B-cell NHL, and further clinical development is warranted. In this review, we summarize the recent clinical developments, clinical implications, and perspectives of CAR T-cell therapy, focusing on B-cell NHL

2009

ABSTRACT first relapse after being treated with chemotherapy alone during CR1. Methods Patients Adults with AML who had achieved CR1 were retrospectively registered in a nationwide AML database, which formed the basis of this study. Statistical analysis Data were retrospectively reviewed and analyzed as of March 2012. Distributions of patients&apos; characteristics between groups were compared using the chi-square test for categorical variables and the Wilcoxon rank-sum test for continuous variables. A Kaplan-Meier survival analysis was performed to estimate the probabilities of overall survival, which was defined as the time from the first relapse to death or the last visit. Differences in overall survival between groups were compared by means of the log-rank test. To compare the outcomes of patients who received allogeneic HCT after relapse and those who did not, we performed landmark analyses by excluding patients who died within 120 days from relapse. The Cox regression model was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). As covariates considered in univariate and multivariate analyses, we selected clinically important factors that were present at the first relapse. All statistical analyses were performed with SPSS software version 11.0.1 (SPSS, Chicago, IL, USA) and EZR (Saitama Medical Center, Jichi Medical University), which is a graphical user interface for R (The R Foundation for Statistical Computing). Results Characteristics of relapsed patients Of the total of 2516 patients, 397 were diagnosed with CBF-AML. Twenty-six patients underwent allogeneic HCT during CR1 [17 patients with t(8;21) and 9 with inv(16)]. Among the 371 patients who were treated with chemotherapy alone during the CR1, 208 (56%) experienced a first hematologic relapse, and analyses were performed in 139 [92 patients with t(8;21) and 47 with inv(16) including three with t(16;16)] for whom additional data were available We investigated the cytogenetic profile at relapse in comparison with that at diagnosis. Cytogenetic data were not available for 10% of the patients because of an insufficient count of mitotic cells or because a chromosome analysis was not performed at relapse. Different cytogenetics were observed in 36% and 28% of those with t(8;21) and inv(16), respectively, and included a decrease in cytogenetic abnormalities (1% and 6%), an increase in cytogenetic abnormalities: numerical change (0% and 11%), an increase in cytogenetic abnormalities: structural change (21% and 0%), and unrelated changes (14% and 11%). Therapeutic strategies and response after relapse Online Supplementary Table S1 and Salvage allogeneic hematopoietic cell transplantation after relapse Of the 139 relapsed patients, 96 (69%), who accounted for 71% and 66% of those with t(8;21) and inv(16), respectively, underwent allogeneic HCT after the first relapse ( Overall survival after the first relapse The median follow-up of surviving patients was 38 months from relapse, and the 3-year overall survival rate after relapse was 48% for the whole group of relapsed patients with CBF-AML ( We performed a landmark analysis to compare overall survival after relapse in patients who underwent allogeneic HCT at any time after relapse and those who did not. S. Kurosawa et al. 1528 haematologica | 2013; 98(10) Multivariate analysis for overall survival after the first relaps