Targeted Intravenous Vs Oral Busulfan in Very Young Children with Thalassemia Major Undergoing Matched Allogeneic Haematopoietic Stem Cell Transplantation Reduces Graft Rejection without Increasing Toxicity

Abstract

Targeted intravenous (IV) Busulfan (TBu) in combination with cyclophosphamide (Cy) is widely used as a preparative regimen in children with thalassemia major (TM) undergoing matched allogeneic haematopoietic stem cell transplantation (HSCT) to reduce toxicity. At our centre, we have been using TBu/Cy regimen since 2011 for very young children and with matched related donors. We have compared the outcome of HSCT in this group of patients with a retrospective cohort (from 1995-2009) of age and risk status matched patients receiving fixed dose oral Bu without PK monitoring. All patients with TM undergoing HSCT with matched related donor between January, 2011 – May, 2018, receiving IV Bu/Cy with anti-thymocyte globulin based conditioning regimen were included in this study. Busulfan levels were monitored after the 1st dose of busulfan and further doses adjusted to achieve a target range of 900-1300um*min. The Bu plasma levels achieved on day 1 and on day 3 were compared with HSCT outcome endpoints including chimerism status on D28, overall and event-free survival (OS, EFS), and graft rejection. There were 52 children, median age of 3 years (range:1-6); 44 class I/II and 8 class III low risk. Bu dose was increased in 35, decreased in 2 and unchanged in 15 patients for dose 3. Target Bu AUC was achieved in 40 patients (77%) on Day 3 while the AUC in the remaining 12 patients (23%) was lower than 900 um*min (range: 543-872). Twenty-three of the 50 evaluable patients showed mixed chimerism (MC) or rejection on day 28; 11/23 (47%) had graft rejection. The OS and EFS were 96% and 79% respectively. Correlation of PK with all demographic variables by univariate analysis did not reveal any significant associations. However, while 11 out of 39 patients (28%) with 9th dose Bu AUC in the lower three quartiles rejected the graft (Q1: <913 (543-906)-à 3; Q2: 936-1100à 2; Q3: 1110-1271à 6), none of the 13 patients (0%) in the highest quartile (>1292 (1299-2656) um*min) rejected the graft (p=0.034). Although none of the 13 patients in Q4 died, 7 had hepatotoxicity (grade 2 and above) and mucositis (grade 2 and above). We then compared the HSCT outcome parameters in these patients with age and Pesaro class matched retrospective cohort of thalassemia patients (n=79) who had received a similar conditioning regimen but with oral Bu without PK guided dose adjustment. There was a trend towards better OS in the TBu cohort compared to the oral Bu (p=0.08) but this did not translate to better EFS due to increased incidence of graft rejection. In conclusion, our data suggests that targeting higher Bu AUCs within the therapeutic window could reduce the risk of graft rejection and improved OS without increasing toxicity. Strategies for rapid dose adjustments after the first dose PK are needed to better achieve these target values to reduce rejections and improve outcome.