Human adenovirus (HAdV) infections constitute a major cause of morbidity in paediatric haematopoietic stem cell transplant (HSCT) patients. New antiviral treatments offer promising perspectives. However, it remains challenging to identify patients at risk for disseminated infection, and who should receive early antiviral intervention. We conducted a longitudinal study of allogeneic HSCT recipients, including weekly HAdV monitoring, to determine the risks factors associated with HAdV infection and dissemination, and to assess whether HAdV loads in stools may be used as surrogate markers for HAdV dissemination. Between September 2010 and December 2011, out of 72 patients, the cumulative incidence rates at day 100 of HAdV digestive infection, systemic infection and related disease were 35.9%, 24.0%, and 18.3%, respectively. In multivariate analysis, the risk factors for HAdV digestive and systemic infection were cord blood and in vitro T-cell depletion. Graft-versus-host disease (GVHD) grade >2 was also associated with systemic infection. In patients with HAdV digestive shedding, GVHD grade >2 and HAdV load in stools were the only risk factors for systemic infection. The median peak levels of HAdV in stool were 7.9 and 4.0 log10 copies/mL, respectively, in patients with HAdV systemic infection and in those without. HAdV monitoring in stools of paediatric HSCT recipients receiving cord blood or in vitro T-cell depleted transplants helps to predict patients at risk for HAdV systemic infection. Our results provide a rationale for randomized controlled trials to evaluate the benefit of anti-HAdV pre-emptive treatments based on HAdV DNA levels in stools.

Introduction: T-cell acute lymphoblastic leukemia (T-ALL) represent 15-20% of childhood/adolescent young adults (AYA) ALL. An intensive chemotherapy is generally needed to obtain the same results than in B-lineage ALL. Day 8 Poor Prednisone Response (PPR) and early resistant disease (refractoriness after induction course or MRD level >10-3 at time point 1 (TP1) and/or TP2) remain particularly challenging as relapses are very difficult to treat especially if they occur early. Nelarabine is a water-soluble prodrug of araG (9-B-arabinofuranosylguanine) which is cytotoxic to T lymphoblasts due to the accumulation of araG nucleotides, especially araGTP, which result in inhibition of ribonucleotide reductase and inhibition of DNA synthesis. Nelarabine was shown to be effective and safe in phase II-III adult and pediatric ALL trials. We describe here a 7 consecutive years experience of nelarabine in “real life” in 3 pediatric / AYA centers. Methods: All children and AYA who received nelarabine in first line therapy or after relapse between 2006 and 2013 were reviewed retrospectively. Classical initial prognostic factors were collected: age, leucocytosis, CNS status, day 8 prednisone response, complete remission (CR) or not, minimum residual disease (MRD) level at TP1 and TP2. Eighty two % of the patients (pts) followed the French FRALLE 2000-T recommendations. Nelarabine, alone or in combination, was used in two groups of pts: group 1: pts in whom nelarabine is given in first line therapy because of high MRD level >10-3 at TP1 and/or TP2 (whatever the level at time of nelarabine infusion) and pts refractory to induction course, and group 2: pts in relapse. Group 1 and 2 are compared for MRD level after nelarabine, number of patients able to go to allogeneic HSCT and overall survival. Finally the safety profile was assessed. Results: 33 T-ALL patients received nelarabine alone (n= 22) or in combination (n= 11, most often with cyclophosphamide and etoposide) from 2006 to 2013. At initial diagnosis, median age was 11.6 y old [3-24], sex ratio 4.5 (M/F 27/6) and median leukocytosis 184.7.109/L [0.1-914]. These patients shared poor risk factors: CNS3 (n=8, 24.1%), D8 PPR (n=23, 69.7%), day 21 M3 bone marrow (n=13, 36.4%), no CR after one induction course (n=6, 18.2%) and MRD level > 10-3 at CR1 (n=15, 42.4%). Regarding group 1 (high MRD level at TP1 and/or TP2 n= 11, refractoriness to induction course n= 5), the status just before nelarabine was: 6 in CR1 with finally MRD <10-3, 5 in CR1 but MRD >10-3 and 5 refractory. Nelarabine was given alone in 12 patients and in combination in 4 patients. MRD level after nelarabine was <10-3 in 12/16 patients. Overall, 11 pts received an allogeneic HSCT and 13/16 (81%) are alive in CR1 at the time of the analysis with a median FU from first nelarabine infusion of 13.7 months [0.8-58.3]. Overall survival is 79.8%+/-10.5 at 5 years. Regarding group 2 (relapsed patients, n= 17), nelarabine was infused at the time of first relapse in 4 patients and in refractory first relapse or more than first relapse in 13 patients. Among these heavily pretreated patients, only 6 obtained a MRD level <10-3 leading to allogeneic HSCT but none of 6 survived. Only one patient survived in CR3 after a success of nelarabine alone and received other chemotherapy without allogeneic HSCT. Regarding toxicities, the only WHO grade III-IV observed side effects are cytopenias (n= 25, 75.8%). Others reported side effects are limited (grade I-II): fever of undetermined origin or infections (n= 7, 21.2%), neurological (n= 6 pts, 18.2%; some of them with more than one side effect: sensory neuropathy in 4, motor neuropathy in 2, headaches in 2, motor-facial neuropathy in 1, ataxia in 1) or muscular (n= 4, 12.1%; 2 myalgia, 1 myositis, 1 amyotrophia), liver toxicities (n= 4, 12.1%; 3 transaminase increases, 1 hyperbilirubinemia). Conclusions: In a non selected population of childhood / AYA high-risk T-ALL, nelarabine was very useful for poor risk patients in first line therapy. The majority of patients received nelarabine as a monotherapy. By contrast nelarabine mostly failed to improve the survival in heavily pretreated relapsed patients. Overall, this study conforts the use of nelarabine in first line T-ALL and high-risk features with acceptable tolerance. The evaluation of nelarabine in selected high-risk patients in a first line setting should be evaluated prospectively to confirm these results. Disclosures Baruchel: JAZZ: Membership on an entity's Board of Directors or advisory committees; ARIAD: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees.