Intensive Chemotherapy Along with Aggressive Supportive Care Can Spare Stem Cell Transplantation in a Subset of Patients without Compromising an Outcome in Infants with Acute Lymphoblastic Leukemia; A Report from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) Trial MLL-10

BACKGROUND: Outcome of infants with acute lymphoblastic leukemia (ALL), especially those with rearrangement of MLL (KMT2A) gene (MLL-r), is extremely poor. A strategy to perform allogeneic hematopoietic stem cell transplantation (HSCT) for all the infants with MLL-r ALL in first remission (1CR) have been tested in the previous Japanese trials MLL96/98/03, however, the improvement was modest. Given the recent evidence of a limited role of HSCT especially in infants lacking poor prognostic factors, efficacy and safety of an intensive chemotherapy and risk stratification to limit HSCT for only infants with high-risk of relapse were evaluated in the JPLSG MLL-10 trial (UMIN000004801). PATIENTS & METHODS: Infants age less than 365 days with ALL were registered in the MLL-10 study and were stratified by their MLL gene status, age at diagnosis, and presence of CNS disease; low-risk (LR), if the patients had germline MLL gene (MLL-g); intermediate-risk (IR), if the patients with MLL-r ALL were age 180 days or older and lack CNS disease; high-risk (HR), if the patients with MLL-r ALL were age RESULTS: A total of 90 eligible infants with ALL were registered in the MLL-10 study between Jan/2011 and Dec/2014; 15 cases were stratified as LR, 19 as IR, and 56 as HR. Remission status was evaluated after 2 chemotherapy courses; 82 (91.1%) achieved 1CR, 3 failed to achieve 1CR, and 5 discontinued the trial before CR evaluation. No early death was observed. With median follow-up period of 1954 days (range, 534-2835 days) in the live patients, 3-year probability of event-free survival (pEFS) and overall survival (pOS) were 70.9% (95% CI, 60.0-79.3%) and 86.6% (77.6-92.2%), respectively. Among the MLL-r cases, 3-year pEFS and pOS were 66.2% (53.9-75.9%) and 83.9% (73.4-90.5%), respectively. According to the risk groups, 3-year pEFS were 93.3% (61.2-99.0%) for LR, 94.4% (66.6-99.2%) for IR, and 56.6% (42.4-68.6%) for HR cases. Regarding the MRD studies, correlation of MRD results in 3 methodologies seemed reasonable, but while flow-MRD could be evaluated in 85 cases, MLL-fusion PCR-MRD (MLL-r cases only) and IgH/TCR PCR-MRD could only be evaluated in 55 and 50 cases, respectively. In the univariable analysis for MLL-r cases, female sex (P=0.04), younger age at diagnosis (P=0.01), and 0.01%< flow-MRD after 2 courses of chemotherapy (P CONCLUSIONS: Introduction of intensive chemotherapy enabled us to spare allogeneic HSCT in 1CR at least in a subset of infants with MLL-r ALL without compromising their outcome. This was accomplished also because of the aggressive supportive care provided to the study cases, such as full hospitalization during and after the intensive treatment phases, intensive use of rasburicase to prevent tumor lysis syndromes, and aggressive infection prophylaxis. However, outcome of HR MLL-r cases is still unsatisfactory, and introduction of novel agents is mandatory for further improvement in the outcome of infants with ALL. Figure Disclosures No relevant conflicts of interest to declare.