D.H. Fowler

Recombinant Human Factor VIIa for Alveolar Hemorrhage Following Allogeneic Stem Cell Transplantation

The mortality rate of alveolar hemorrhage (AH) after allogeneic hematopoietic stem cell transplantation is greater than 60% with supportive care and high-dose steroid therapy. We performed a retrospective cohort analysis to assess the benefits and risks of recombinant human factor VIIa (rFVIIa) as a therapeutic adjunct for AH. Between 2005 and 2012, 57 episodes of AH occurred in 37 patients. Fourteen episodes (in 14 patients) were treated with steroids alone, and 43 episodes (in 23 patients) were treated with steroids and rFVIIa. The median steroid dose was 1.9 mg/kg/d (interquartile range [IQR], 0.8 to 3.5 mg/kg/d; methylprednisolone equivalents) and did not differ statistically between the 2 groups. The median rFVIIa dose was 41 μg/kg (IQR, 39 to 62 μg/kg), and a median of 3 doses (IQR, 2 to 17) was administered per episode. Concurrent infection was diagnosed in 65% of the episodes. Patients had moderately severe hypoxia (median PaO2/FiO2, 193 [IQR, 141 to 262]); 72% required mechanical ventilation, and 42% survived to extubation. The addition of rFVIIa did not alter time to resolution of AH (P = .50), duration of mechanical ventilation (P = .89), duration of oxygen supplementation (P = .55), or hospital mortality (P = .27). Four possible thrombotic events (9% of 43 episodes) occurred with rFVIIa. rFVIIa in combination with corticosteroids did not confer clear clinical advantages compared with corticosteroids alone. In patients with AH following hematopoietic stem cell transplantation, clinical factors (ie, worsening infection, multiple organ failure, or recrudescence of primary disease) may be more important than the benefit of enhanced hemostasis from rFVIIa.

Obesity Provides a Permissive Milieu in Inflammation-Associated Carcinogenesis: Analysis of Insulin and IGF Pathways

Current dogma suggests that the positive correlation between obesity and cancer is driven by white adipose tissue that accompanies obesity, possibly through excess secretion of adipokines. However, recent studies in fatless A-Zip/F-1 mice, which have undetectable adipokine levels but display accelerated tumor formation, suggest that adipokines are not required for the enhanced tumor development. The A-Zip/F-1 mice are also diabetic and display elevated circulating levels of other molecules frequently associated with obesity and carcinogenesis: insulin, insulin-like growth factor-1, and inflammatory cytokines. Therefore, we postulate that the pathways associated with insulin resistance and inflammation, rather than adipocyte-derived factors, may represent key prevention or therapeutic targets for disrupting the obesity-cancer link.

234: Rapamycin generated donor Th2/Tc2 cells prevent graft rejection by inhibition of alloreactivity and not by deletion of alloreactive T cells

donor chimerism was day 28 for CD33 and day 180 for CD3 . AGVHD occurred in 42/60 (70%) pts (grade I in 14 and grades II-IV in 28), and cGVHD occurred in 28/52 (54%); 12 pts developed extensive cGVHD. 14 pts required donor lymphocyte infusion for disease progression. 100-day NRM was 10% (all from aGVHD); another 2 patients died of disease progression. After day 100, most pts died from disease progression or infection related to cGVHD. Kaplan-Meier probabilities for overall survival (OS) and progression free survival (PFS) at one year were 61% and 48%, respectively with median follow up of 505 days (range 31-2029). OS at 2 and 3 years was 45% and 36%. In univariate analysis, the development of cGVHD significantly correlated with improved OS (p 0.02) and PFS (p 0.01). Although CD34 and CD3 doses showed no significant association with development of cGVHD, higher doses of both were associated with development of aGVHD (p 0.01 and 0.04 respectively) and higher CD34 doses (6.8 vs 9.4 10/kg) were associated with development of higher grades of aGVHD (grades II-IV versus grades 0-I) (p 0.01). Incremental increases in CD34 dose were associated with an increased hazard ratio for death; however, a dose above 8 10 CD34 /kg was associated with lower probability of relapse (p 0.04). NM conditioning has a role in alloPBSCT and further investigation to optimize disease indications and CD34 dosing is needed.