Poster Board III-149
Following administration of ex-vivo expanded T cells, the FDA currently recommends at least 4 hours of recipient monitoring to detect early infusion reactions. Recent catastrophic reactions to “first in man” biological agents have emphasized the importance of this rule for initial studies of new products, but its value for longer established agents is less evident. We have therefore reviewed the incidence and nature of infusion-related adverse events (AEs) associated with administration of ex-vivo expanded T cell products (antigen specific CTLs, allodepleted T cells, and genetically modified T cells) on Investigational New Drug (IND) studies in our center over the last decade. From 1998 to 2008, we infused 381 T cell products to 180 recipients who were enrolled on 18 such studies, receiving T cells targeting malignancies or post-transplant viral infections. The age of these recipients ranged from 9 months to 80 years. Cell doses were protocol specific and ranged from 104/kg up to 3 ×108/m2. Patients were premedicated with diphenhydramine (0.5-1mg/kg) and acetaminophen (10mg/kg up to a maximum of 625mg) prior to infusion. All cellular products were cryopreserved and administered intravenously over 1-15 minutes immediately after thawing. There were no Grade 3-4 infusion reactions during initial monitoring or 24 hour follow-up. Twenty four grade 1-2, non-severe adverse events (AEs) occurred in 21 infusions either during or immediately following infusion (up to 6 hours). The most common AEs were nausea and vomiting (10/24; 41.6%), most likely due to DMSO used in cryopreservation of T cell products, and hypotension (20.8%), attributable to diphenhydramine pre-medication. An additional 22 non-severe events within 24 hours of infusion were reported, the most common of which were fever (with negative blood cultures)/chills/constitutional symptoms (6/22; 27.3%) and nausea/vomiting (4/22; 18.2%) Overall, a total of 46 non-severe adverse events were noted within 24 hours of T cell product infusion (12.56%). A Fisher's exact analysis of all T cell product infusions grouped by patient age, patient ethnicity, or cell source revealed no association with increased risk. T cells from both allogeneic and autologous sources produced similar adverse events in terms of type, frequency, and severity, and allogeneic cells that were mismatched at > 2 HLA antigens had the same AEs as donor T cells matched at 5/6 or 6/6 HLA loci. We further analyzed the data using Poisson regression and the general estimating equation (GEE) model for correlated counts, to seek associations that may have been missed because AEs within a subject may not be statistically independent. By this analysis, we found decreased risks of adverse events in older patients (IRR 0.98; 95% CI 0.96-1.00; p=0.05), and increased risks of immediate (defined as occurring during the monitoring period) infusion-related events in patients reporting allergies (IRR 2.72; 95% CI 1.00-7.40; p=0.05). We thus conclude that infusion of the ex-vivo expanded T cell products used in these studies is a safe procedure associated with no severe reactions, that it is safe in the outpatient setting and that monitoring can be limited to an hour after infusion. As many of the AEs observed were due to diphenhydramine premedication, a lower dose (0.25mg/kg) of this agent may be preferred.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.