7032 Background: Decitabine is an efficient hypomethylating agent approved by the FDA for the treatment of MDS. In a Phase III trial that studied a 3-day dosing regimen, the overall improvement (IWG 2000: complete response [CR] + partial response [PR] + hematologic improvement [HI]) rate for decitabine was 30% versus 7% in the supportive care arm (Cancer 2006:106:1794); responses were seen in all International Prognostic Scoring System (IPSS) risk groups. A single center Phase II trial in patients (pts) with MDS, examining an alternative outpatient regimen of decitabine administered at 20 mg/m2 IV over 1 hour once daily for 5 days every 4 weeks, resulted in an overall improvement rate (IWG 2006: CR + marrow CR (mCR) + PR + HI) of 72% (Cancer 2007:109:265). The purpose of this trial was to examine the efficacy and safety of this alternative dosing regimen in a multicenter setting. Methods: This Phase II trial enrolled pts with all FAB classifications of MDS and IPSS scores ≥ 0.5 with an ECOG performance status of 0–2. An expert review of responses according to IWG 2006 criteria was performed. Results: Baseline patient characteristics: median age 72 yrs, 11% had secondary MDS, 27% with prior MDS disease-modifying therapy, and 29% had poor risk cytogenetics. The overall improvement rate was similar across IPSS risk groups (Intermediate-1 [n=52]: 50%; Intermediate-2 [n=23]: 61%; High Risk [n=23]: 43%). 82% of pts who experienced clinical improvement did so by cycle 2. The overall improvement rate was 51% for pts with de novo MDS, 45% for secondary MDS, and 44% for pts who received prior disease-modifying agents. The safety profile was consistent with previous studies. Conclusions: This multicenter trial examining the alternative 5-day decitabine dosing schedule compares favorably with that of the 3-day dosing regimen, provides validation and generalizability of the previously published single center trial and confirms that the alternative schedule is safe and effective in pts with MDS including those who have poor prognostic factors. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration MGI Pharma MGI Pharma MGI Pharma MGI Pharma MGI Pharma, Pharmion
YARS2 variants have previously been described in patients with myopathy, lactic acidosis and sideroblastic anemia 2 (MLASA2). YARS2 encodes the mitochondrial tyrosyl-tRNA synthetase, which is responsible for conjugating tyrosine to its cognate mt-tRNA for mitochondrial protein synthesis. Here we describe 14 individuals from 11 families presenting with sideroblastic anemia and YARS2 variants that we identified using a sideroblastic anemia gene panel or exome sequencing. The phenotype of these patients ranged from MLASA to isolated congenital sideroblastic anemia. As in previous cases, inter- and intra-familial phenotypic variability was observed, however, this report includes the first cases with isolated sideroblastic anemia and patients with biallelic YARS2 variants that have no clinically ascertainable phenotype. We identified ten novel YARS2 variants and three previously reported variants. In vitro amino-acylation assays of five novel missense variants showed that three had less effect on the catalytic activity of YARS2 than the most commonly reported variant, p.(Phe52Leu), associated with MLASA2, which may explain the milder phenotypes in patients with these variants. However, the other two missense variants had a more severe effect on YARS2 catalytic efficiency. Several patients carried the common YARS2 c.572 G>T, p.(Gly191Val) variant (minor allele frequency =0.1259) in trans with a rare deleterious YARS2 variant. We have previously shown that the p.(Gly191Val) variant reduces YARS2 catalytic activity. Consequently, we suggest that biallelic YARS2 variants, including severe loss-of-function alleles in trans of the common p.(Gly191Val) variant, should be considered as a cause of isolated congenital sideroblastic anemia, as well as the MLASA syndromic phenotype.
Storytelling is a deeply human act—ancient, universal, and familiar. But in this data-driven “Information Age,” is there still room for narrative? As oncologists, we often feel overclocked, increasingly forced to microtask and live by the business world's mantra of “faster, cheaper, better,” while our carefully honed humanistic clinical skills are coldly commoditized into Relative Value Units, our aptitude measured with tools that emphasize form over substance. In such an environment, can we still afford the inefficiency of anecdotes? Some might argue that we no longer need patient and physician narratives to inform care; instead, accurate molecular subtyping of tumors, good pharmaceutical agents, and rigorous clinical trial results are enough. Yet stories and reflections about being a doctor or being a patient remain important and instructive even in this era of molecular cancer medicine, even in the face of our increasing reliance on high-tech diagnostics and narrowly targeted smart therapeutics. Amid the pressures of rapidly changing practice patterns and the daily emotional challenges of working with seriously ill and dying patients, the acts of reflection and storytelling can also help keep us sane. Here I discuss the persistent importance of narrative in the context of the “Art of Oncology” forum of the Journal of Clinical Oncology.
