Detectable Minimal Residual Disease before Haematopoietic Stem Cell Transplantation Predicts Extremely Poor Prognosis in Children with Acute Lymphoblastic Leukaemia.

The level of minimal residual disease (MRD) prior to allogeneic haematopoietic stem cell transplantation (HSCT) was shown to be an independent prognostic factor for the outcome of paediatric patients with high-risk acute lymphoblastic leukemia (ALL). Retrospective studies which used (semi-)quantitation of clone-specific immunoglobulin/T-cell receptor (Ig/TCR) rearrangements documented feasibility and practicality of such an approach. Recently, this approach was disputed by Imashuku et al (BMT 2003) due to great occurrence of the clonal evolution and generally high MRD levels prior HSCT in their cohort. In our prospective study, MRD before and after HSCT was monitored in a cohort of 36 children with ALL consecutively transplanted in our centre between VIII/2000 and VII/2004. We used a quantitative real-time PCR approach introduced and standardised by European Study Group on MRD in ALL. In 25 of 36 patients MRD level prior HSCT was assessed (9 patients lacked adequately sensitive Ig/TCR target; two lacked analysable DNA prior HSCT). Seventeen patients were MRD-negative prior HSCT (including two with MRD level below the quantitative range 10(−4)) and 8 were MRD-positive up to 9x10(−2). In the MRD-positive subgroup, 7 events (6 relapses) occurred post-transplant in striking contrast to only one relapse in MRD-negative subgroup (EFS log-rank p<0.0001). MRD proved to be the only significant prognostic factor in a multivariate analysis (p<0.0001). Adoptive immunotherapy including donor lymphocyte infusions in patients with adverse dynamics of MRD after HSCT had only limited and/or temporary effect. Clonal evolution did not present a problem precluding MRD monitoring in any of patients suffering a post-transplant relapse. We show that MRD quantitation using clonal Ig/TCR rearrangements represents a feasible approach for the risk assessment in paediatric ALL patients undergoing allogeneic HSCT. However, our ability to respond to detectable MRD levels after HSCT and to avert an impending relapse is very limited. The change of the approach to MRD-positive patients prior HSCT is necessary because of very questionable benefit of HSCT in these children. Supported by grants MSM0021620813, FNM 9735 and GAUK 62/2004.