Sunday March 27, 2022 - 13:15 to 14:25
Mutations in Latent Membrane Protein 1 of Epstein Barr Virus are Associated with Increased Risk of Post-transplant Lymphoproliferative Disorder
Olivia M. Martinez1, Sheri M. Krams1, Mark Robien2, Mary Gay M. Lapasaran1, Matt Arvedson1, Andrea Reitsma1, Ken Weinberg1, Scott Boyd1, Brian Armstrong3, Clare Twist4, Dita Gratzinger1, Brent Tan 1, Amber Trickey1, Michelle Sever3, Merideth Brown2, Daniel Bernstein1, Carlos Esquivel1, CTOC-06 Investigators5,6,7,8,9,10.
1Surgery, Pediatrics and Pathology, Stanford University School of Medicine, Stanford, CA, United States; 2NIAID, NIH, Rockville, MD, United States; 3Rho, Durham, NC, United States; 4Roswell Park, Buffalo, NY, United States; 5Surgery, Pediatrics, UT Southwestern, Dallas, TX, United States; 6Surgery, University of Pittsburgh, Children's Hospital, Pittsburgh, PA, United States; 7Surgery, Pediatrics, UCLA, Los Angeles, CA, United States; 8Surgery, University of Miami, Miami, FL, United States; 9Surgery, Georgetown University, Georgetown, CA, United States; 10Pediatrics, University of Cincinnati, Cinncinati, OH, United States
Clinical Trials in Organ Transplantation in Children.
Post-transplant lymphoproliferative disorders (PTLD) remain a serious problem in the pediatric transplant population. Clinical Trials of Organ Transplantation in Children (CTOTC)-06 was a prospective NIH-sponsored multi-institutional study intended to identify viral and immune biomarkers of Epstein-Barr virus (EBV)-associated PTLD. Here we report analysis of the complete CTOTC-06 data set.
944 pediatric subjects were enrolled at 7 centers in the US from 2014-18 of whom 872 received a transplant: liver (n=421), kidney (n=219), heart (n=180), or intestine (n=52). Immunosuppression and anti-viral therapy were per each center's standard protocol. Mean age at transplant was 6.7±6.3 years (range <1-21 years) with 54% males and 46% females. Over 4700 blood samples were prospectively collected at enrollment or transplant, every 3 months during the first 2 years, twice yearly thereafter, and at PTLD diagnosis. DNA was isolated from whole blood and the cytoplasmic region of the EBV oncogene LMP1, PCR amplified, cloned and sequenced to determine the presence of G212S and S366T constitutively active mutations.
34 subjects (3.9%) reached the primary endpoint of biopsy-proven EBV+ PTLD. Incidence varied by organ type: small intestine 13.5%, heart 4.4%, kidney 3.2%, and liver 2.9%. The mean time post-transplant to diagnosis of EBV+ PTLD was 564.9±525.3 days (range 51-2303) and the mean time from EBV positivity to PTLD was 384.1±526.6 days (range 0-2310). PTLD WHO subtypes were early lesion (38.2%), monomorphic (44.1%) and polymorphic (17.7%). EBV serostatus of donors (D) and recipients (R) for those who developed PTLD vs all transplanted subjects was D+R+ (26.5% vs 43%), D+R- (41.2% vs 23.7%), D-R+ (8.8% vs 11.2%), D-R- (8.8% vs 8.3%) and unknown (14.7% vs 13.8%). DNA was available for LMP1 sequencing from 32 PTLD cases and 62 matched controls. Both mutations (G212S and S366T) were present in 31 of 32 PTLD cases (96.9%) and in 45 of 62 matched controls (72.6%) (p=0.005, OR=11.7, 95% CI 1.5, 92.6). For EBV+ PTLD, the presence of both mutations had a positive predictive value of 5.1% and a negative predictive value of 99.5% with a very high sensitivity of 96.9% and a modest specificity of 27.4%.
In this prospective, multicenter clinical trial we demonstrate a significant association between the presence of both LMP1 mutations G212S and S366T and the development of EBV+ PTLD. Pediatric transplant recipients who lacked both mutations in LMP1 had a very high probability of not developing PTLD. Thus, determination of LMP1 mutation status post-transplant could be informative in stratifying patients for risk of PTLD development.