Recaída de la leucemia aguda linfoblástica en la infanciaresultados actuales del tratamiento y nuevas alternativas terapéuticas

Laburpena

Acute lymphoblastic leukemia (ALL) is the most common malignant disease in childhood. Even though results from first line treatment have dramatically improved during recent decades, relapse remains the main cause of treatment failure with overall survival (OS) below 50% after first relapse in patient undergoing standard treatment approaches, including chemotherapy, radiotherapy and allogeneic stem cell transplantation (SCT) from an HLA compatible donor. As a consequence, ALL remains one of the major causes of cancer-related death among children. Incidence of relapse is low and, in order to gain knowledge and improve treatment results, collaborative efforts are needed in order to elaborate coordinated diagnostic and therapeutic approaches and to collect data allowing the analysis of results. With this aim, the “LAL/SEHOP-PETHEMA 2015” recommendation guidelines were developed by the leukemia working group of the Spanish Society of Pediatric Hematology and Oncology (SEHOP). In order to improve current results and reduce the incidence of long-term adverse events it will be necessary to incorporate novel drugs and treatment approaches, and close collaboration among experts in ALL relapse and basic researchers is crucial. New immunotherapy-based treatment modalities such as monoclonal antibodies (MAs) and chimeric antigen receptor T-cell (CART) therapy have recently been incorporated as treatment options for ALL. Objectives. 1) To evaluate early clinical experience in Spain with the MAs blinatumomab and inotuzumab oaogamycin (InO) in children with ALL. 2) To describe a pre-clinical experience directed to identify novel targets for the applications of new modified T-cell strategies (CART). 3) To analyze recent treatment outcomes after standard treatment of children with first relapse of ALL in Spain. 4) To evaluate the role of haploidentical donor as an alternative to HLA-compatible SCT as consolidation of children with second complete remission (CR2) of ALL. Methods. 1) Retrospective analysis of treatment results (rate of response, toxicity and outcome) from 29 children from 11 Spanish institution undergoing treatment with blinatumomab and InO. 2) Development of an anti-CD22 antibody and a membrane-distal epitope of the CD22 antigen targeted CART and evaluation of its efficacy in vitro and in vivo. 3) Analysis of OS and event free survival (EFS) rates from 76 children with first relapse of ALL undergoing standard treatment according to the “LAL/SEHOP-PETHEMA 2015” guidelines. 4) Comparative analysis of outcome in children with ALL undegoing SCT in CR2 from haploidental (n = 25) versus HLA-compatible donors (n = 51). Conclusions. 1) Blinatumomab and InO were able to induce complete remissions in 47.6% of heavily pre-treated advanced stage ALL patients. 2). Our novel CART hCD22.7, with high affinity for a membrane-distal epitope of CD22, efficiently eliminate ALL samples in vitro and in vivo. 3) After a median follow up of 12.5 months, with standard treatment for ALL first relapse, we found 3-year EFS and OS rates of 40.1 ± 12.5% and 54.8 ± 14.9%, respectively (59.3±16.8% and 71.2±15.2% for standard risk; 13.5 ± 14.8% and 33.3 ± 23.9% for high risk patients). According to recent data reported from two prospective randomized studies, the authors claim to provide accessibility to blinatumomab for all children after high risk first relapse of ALL in Spain. 4) We found no differences in treatment outcome among patients undergoing haploidentical versus HLA-compatible donor SCT. Chronic graft versus host disease had protective impact, and minimal residual disease ≥ 0.01% before SCT had unfavorable impact on leukemia free survival.