Acute lymphoblastic leukemia in infants: a quarter century of nationwide efforts in Japan.

Acute lymphoblastic leukemia (ALL) with KMT2A gene rearrangement (KMT2A-r) in infants is a biologically and clinically unique disease and one of the most difficult-to-cure forms of pediatric leukemia. Continuing nationwide efforts by conducting multicenter clinical trials have been carried out in Japan since the mid-1990s by introducing allogeneic hematopoietic stem cell transplantation (HSCT) in first remission, which led to a modest improvement in outcome of infants with KMT2A-r ALL. Because of the emerging evidence that HSCT does not benefit every infant with KMT2A-r ALL, the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) trial MLL-10 introduced risk stratification using age and presence of CNS leukemia and introduced intensive chemotherapy including high-dose cytarabine in early consolidation; indication of HSCT was restricted to the patients with high-risk features. The trial resulted in excellent 3-year event-free survival of 66.2% (standard error [SE], 5.6%) and overall survival of 83.9% (SE, 4.3%) for 75 patients with KMT2A-r ALL recruited between 2011 and 2015. This Japanese experience and the results of the infant ALL trials worldwide suggest the importance of introducing effective therapy in the early phase of therapy, thus clearing minimal residual disease as rapidly as possible. However, further improvement in outcome is unlikely with conventional treatment approaches. Introduction of biology-driven novel agents and/or immunotherapies through international collaboration would be key solutions to overcome the disease.