Recent progress in the treatment of infant acute lymphoblastic leukemia

Abstract

Treatment of infants with acute lymphoblastic leukemia (ALL), especially those with mixed lineage leukemia (MLL) rearrangement (MLL-r), which account for approximately 80% of cases, is still a major challenge for pediatric hematologists and oncologists worldwide. Continuing efforts by collaborative clinical study groups in Europe, North America, and Japan have rescued approximately half of the MLL-r ALL patients with intensive chemotherapy with or without allogeneic hematopoietic stem cell transplantation. Recent progress has clarified the unique mechanism of MLL-r ALL: the aberrant methylation and histone modifications via DOT1L and other related molecules by MLL fusion proteins lead to leukemogenetic gene expression, thus to overt leukemia. In order to overcome this dismal subtype of ALL, novel targeted therapy based on leukemia biology is urgently needed. Due to the extreme rarity of the disease, collaboration between the study groups in Europe (Interfant), North America (Children's Oncology Group), and Japan (Japanese Pediatric Leukemia/Lymphoma Study Group) is under way.Key words acute lymphoblastic leukemia, epigenetics, hematopoietic stem cell transplantation, infant, mixed lineage leukemia.Acute lymphoblastic leukemia (ALL), a malignant disorder of lymphoid progenitor cells, is the most common type of malignant neoplasms in children and adolescents, with approximately 444-532 cases diagnosed annually in Japan. 1 Optimal use of "old drugs", developed between the 1950s and 1970s under successive collaborative clinical trials, has improved the outcome of childhood ALL to achieve an event-free survival (EFS) rate of 80.4-87.2% and an overall survival (OS) rate of 91.8-93.5% in recently completed clinical trials. [2][3][4][5] The progress in the treatment of infant ALL (diagnosed at age <12 months), however, is lagging behind compared with the treatment of children ≥1 year: EFS and OS remain at 41.7-50.9% and 44.8-60.5%, respectively (Table 1). 9,[11][12][13] In this review, advances in the pathobiology and clinical management of ALL in infants is described. Epidemiology and characteristicsInfant ALL accounts for <5% of childhood ALL, with 20-25 new cases diagnosed annually in Japan. In children ≥1 year, ALL comprises 75-80% of all childhood leukemia because of the high peak incidence of B-lineage ALL between the age of 2 and 5 years, with a predominance in boys. In contrast, the incidence of ALL in infants is the same as that of acute myeloid leukemia (AML), with a slight predominance in girls. 1,11 Biologically and clinically, infant ALL consists of two distinct subtypes: one involves rearrangements of mixed lineage leukemia (MLL also called KMT2A), which accounts for approximately 80% of infant ALL; and the other with germline MLL. Infant ALL with rearranged MLL (MLL-r) is a highly aggressive leukemia with high white blood cell (WBC) count and frequent involvement of extramedullary sites including the central nervous system (CNS) at diagnosis. 9,11 In addition, MLL-r ALL has a very immature CD10-ne...

Treatment and biology of pediatric acute lymphoblastic leukemia

“…The main contributors to this dramatic improvement are the availability of better supportive care, treatment stratification based on relapse risk and the biological features of leukemic cells, and the accumulation of evidence uncovered by clinical trials through nationwide and international collaboration. We herein review the history, current status, and future prospects for the treatment of pediatric ALL, focusing on interventions and biology while excluding infant ALL and relapsed ALL, which have been reported on elsewhere …”

DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge

“…DOT1L is the only non-SET domain HKMT and it is the only enzyme responsible for mono-, di- and trimethylation of H3K79, leading to transcriptional activation of certain oncogenes [102,103,104,105,106,107]. It is mainly involved in myeloid lymphoid leukemia with MLL rearrangements by favoring transcription of HOX (subset of homeotic genes) and MEIS (Meis homeobox 1) genes involved in acute leukemia development [105,106,108]. Therefore, medicinal chemistry efforts for DOT1L inhibition have led to the first HMTi in clinics, compound ( 29 ) that completed phase I clinical trials for leukemia treatment and myelodysplastic syndromes (NCT02141828, NCT01684150).…”

Haploidentical peripheral blood stem cell transplantation without irradiation or busulfan after reduced‐intensity conditioning for KMT2A(MLL)‐rearranged infant B‐cell precursor acute lymphoblastic leukemia: Report of two cases

“…Infant BCP‐ALL with KMT2A(MLL) gene R ( KMT2A‐R ) is characterized by high leukocyte count at diagnosis, CNS involvement, hepatosplenomegaly, and lack of CD10 expression . The prognosis of infant BCP‐ALL with KMT2A‐R is usually poor, with a cure rate of less than 50%, even for those who receive modern treatment scheme designed specifically for infant BCP‐ALL …”

“…Recent infant‐specific clinical studies introduced allogeneic HSCT during the first remission . Allogeneic HSCT using MAC immediately after remission improves prognosis .…”

“…Recent infant‐specific clinical studies introduced allogeneic HSCT during the first remission . Allogeneic HSCT using MAC immediately after remission improves prognosis . In a nationwide Japanese multi‐institutional clinical study, the MLL03 study, UCBT with BU‐based MAC shortly after remission resulted in a promising cure rate .…”