Acute myelogenous leukemia (AML) is a high-risk hematopoietic malignancy caused by a variety of mutations, including genes encoding the cohesin complex. Recent studies have demonstrated that reduction in cohesin complex levels leads to enhanced self-renewal in hematopoietic stem and progenitors (HSPCs). We sought to delineate the molecular mechanisms by which cohesin mutations promote enhanced HSPC self-renewal since this represents a critical initial step during leukemic transformation. We verified that RNAi against the cohesin subunit Rad21 causes enhanced self-renewal of HSPCs in vitro through derepression of Polycomb Repressive Complex 2 (PRC2) target genes, including Hoxa7 and Hoxa9. Importantly, knockdown of either Hoxa7 or Hoxa9 suppressed self-renewal, implying both are critical downstream effectors of reduced cohesin levels. We further demonstrate that the cohesin and PRC2 complexes interact and are bound in close proximity to Hoxa7 and Hoxa9. Rad21 depletion resulted in decreased levels of H3K27me3 at the Hoxa7 and Hoxa9 promoters, consistent with Rad21 being critical to proper gene silencing by recruiting the PRC2 complex. Our data demonstrates that the cohesin complex regulates PRC2 targeting to silence Hoxa7 and Hoxa9 and negatively regulate self-renewal. Our studies identify a novel epigenetic mechanism underlying leukemogenesis in AML patients with cohesin mutations.

Veno-occlusive disease (VOD) is an early and serious complication of hematopoietic cell transplantation (HCT) that is associated with inferior survival, particularly when it is complicated by multi-organ failure (severe VOD). We evaluated the efficacy of defibrotide in the treatment of severe VOD using observational data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Eight thousand three hundred forty-one patients treated by HCT between 2008 and 2011 were identified from the CIBMTR clinical database; 3.2% met criteria for VOD and 1.2% met criteria for severe VOD. Patients with a diagnosis of VOD as reported to the CIBMTR by their transplanting centers, who had no prior history of cirrhosis, and who had a maximum total bilirubin >2.0mg/dl by day +100 post-HCT were selected for study. Severe VOD was defined as VOD occurring in the setting of renal impairment requiring dialysis or any non-infectious pulmonary abnormality. Patients with severe VOD were divided into two groups for analysis: those treated with defibrotide (n=41) and those not treated with defibrotide (n=55). Patients in the non-defibrotide group were older, were more likely to be male, were more likely to have a history of previous fungal infection, and had a higher proportion of clinically significant pre-existing disease or organ impairment. Survival at day +100 was 39% (95% CI: 24.8–54.3%) in patients receiving defibrotide and 30.9% (95% CI: 19.5% – 43.6%) in those not receiving defibrotide. Resolution of VOD at day +100 was 51% in the defibrotide group, and 29% in the non-defibrotide group (difference 22.1%, 95% CI: 2.6% – 42%). The results of our study are consistent with previously reported experiences with defibrotide, confirm the poor outcome of this syndrome, and suggest defibrotide is effective in the treatment of severe VOD.

A risk score identifying patients at high risk for veno-occlusive disease (VOD) may aid efforts to study preventive strategies for this uncommon complication of hematopoietic cell transplantation (HCT). Patients receiving a first allogeneic HCT between 2008 and 2013 as reported to the Center for International Blood and Marrow Transplant Research (N = 13,097) were randomly divided into training and validation sets. Independent prognostic factors for development of VOD by day +100 after HCT were identified with a multivariate logistic regression model. A risk score was constructed in the training set using the significant factors and confirmed in the validation set. Baseline characteristics of the training and validation sets were balanced. In total, 637 patients (4.9%) developed VOD by day +100. Younger age, positive hepatitis B/C serology, lower Karnofsky performance scale score, use of sirolimus, disease, disease status at transplant, and conditioning regimen were independent prognostic factors. Myeloablative conditioning regimens were associated with higher risk of VOD. Busulfan-based myeloablative conditioning regimens guided by pharmacokinetic monitoring were associated with higher risk than those without pharmacokinetic monitoring. Patients were stratified into 4 distinct, statistically significantly different groups by their risk score percentile. This pretransplant risk score successfully stratified allogeneic HCT patients by risk of developing VOD, was validated in an independent set, and demonstrated strong discriminatory ability to identify a high-risk cohort.

Cytokine-based mobilization in light chain (AL) amyloidosis is frequently complicated by fluid overload, weight gain, cardiac arrhythmias, and peri-mobilization mortality. We analyzed hematopoietic progenitor cells (HPC) mobilization outcomes in 49 consecutive AL amyloidosis patients at our institution between 2004 and 2013 with granulocyte colony-stimulating factor (G) (10 μg/kg/day) (n = 25) versus an institutional protocol to limit G exposure using plerixafor (P) (.24 mg/kg s.c. starting day 3 of G 10 μg/kg) (n = 24). G+P strategy yielded higher total CD34(+) cells/kg (12.8 × 10(6) versus 6.3 × 10(6); P < .001) and CD34(+) cells/kg collected on day 1 (10.8 × 10(6) versus 4.9 × 10(6), P = .004) compared with the G cohort. More G+P patients collected ≥5 × 10(6) CD34(+) HPCs/kg (22 versus 16, P = .02) and ≥ 10 × 10(6) CD34(+) HPCs/kg (13 versus 5, P = .01). Four patients (16%) had mobilization failure with G; none with G+P. Peri-mobilization weight gain was lower with G+P strategy (median weight gain 1 versus 7 pounds, P = .009). Numbers of apheresis sessions (median, 1 versus 1, P = .52), number of hospitalization days (median, 1.1 versus 1.6, P = .52), transfusions, use of intravenous antibiotics, and cardiac arrhythmias were similar. In conclusion, our study demonstrates that upfront use of G+P as a mobilization strategy results in superior HPC collection, no mobilization failures, and less weight gain than G alone.

Gemcitabine is an antitumor agent with broad clinical application. The most common cutaneous toxicities are mild rash and pruritus; however, a severe 'pseudocellulitis' rash, which resembles infectious cellulitis in clinical presentation, has increasingly been recognized as a rare complication of this agent. Though the specific pathophysiology related to this condition is not clear, it has been observed to occur primarily in regions of significant lymphadenopathy or prior radiation exposure typically after 24-48 h following administration of gemcitabine. It is a self-limiting reaction, with most cases resolving within two to seven days of onset without any specific treatment for the rash. Treatment with gemcitabine may be safely continued in patients with this complication, though recurrence of the rash is common following repeated doses. We report a case of biopsy confirmed gemcitabine associated pseudocellulitis in a patient treated for metastatic pancreatic adenocarcinoma. Knowledge of this complication is important to avoid unwarranted hospitalizations and antibiotic use in patients treated with gemcitabine.