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.
Acute myeloid leukemia (AML) accounts for 25% of pediatric leukemia and affects approximately 180 patients annually in Japan. The treatment outcome for pediatric AML has improved through advances in ...chemotherapy, hematopoietic stem cell transplantation (HSCT), supportive care, and optimal risk stratification. Currently, clinical pediatric AML studies are conducted separately according to the AML subtypes: de novo AML, acute promyelocytic leukemia (APL), and myeloid leukemia with Down syndrome (ML‐DS). Children with de novo AML are treated mainly with anthracyclines and cytarabine, in some cases with HSCT, and the overall survival (OS) rate now approaches 70%. Children with APL are treated with an all‐trans retinoic acid (ATRA)‐combined regimen with an 80–90% OS. Children with ML‐DS are treated with a less intensive regimen compared with non‐DS patients, and the OS is approximately 80%. HSCT in first remission is restricted to children with high‐risk de novo AML only. To further improve outcomes, it will be necessary to combine more accurate risk stratification strategies using molecular genetic analysis with assessment of minimum residual disease, and the introduction of new drugs in international collaborative clinical trials.
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. 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 trial MLL‐10 introduced risk stratification using age and presence of central nervous system 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, 5.6%) and overall survival of 83.9% (standard error, 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.
Acute Myeloid Leukemia (AML) is the second most common type of leukemia in children. Recent advances in high-resolution genomic profiling techniques have uncovered the mutational landscape of ...pediatric AML as distinct from adult AML. Overall survival rates of children with AML have dramatically improved in the past 40 years, currently reaching 70% to 80% in developed countries. This was accomplished by the intensification of conventional chemotherapy, improvement in risk stratification using leukemia-specific cytogenetics/molecular genetics and measurable residual disease, appropriate use of allogeneic hematopoietic stem cell transplantation, and improvement in supportive care. However, the principle therapeutic approach for pediatric AML has not changed substantially for decades and improvement in event-free survival is rather modest. Further refinements in risk stratification and the introduction of emerging novel therapies to contemporary therapy, through international collaboration, would be key solutions for further improvements in outcomes.
Diagnosis, treatment, response monitoring, and outcome of pediatric acute myeloid leukemia (AML) have made enormous progress during the past decades. Because AML is a rare type of childhood cancer, ...with an incidence of approximately seven occurrences per 1 million children annually, national and international collaborative efforts have evolved. This overview describes these efforts and includes a summary of the history and contributions of each of the main collaborative pediatric AML groups worldwide. The focus is on translational and clinical research, which includes past, current, and future clinical trials. Separate sections concern acute promyelocytic leukemia, myeloid leukemia of Down syndrome, and relapsed AML. A plethora of novel antileukemic agents that have emerged, including new classes of drugs, are summarized as well. Finally, an important aspect of the treatment of pediatric AML--supportive care--and late effects are discussed. The future is bright, with a wide range of emerging innovative therapies and with more and more international collaboration that ultimately aim to cure all children with AML, with fewer adverse effects and without late effects.
Background The long-term outcome of X-linked hyper-IgM syndrome (XHIM) caused by mutations in CD40LG is poor, and the only curative treatment is hematopoietic stem cell transplantation (HSCT). ...Objective We sought to determine the clinical features and factors affecting outcomes in patients with XHIM. Methods We enrolled and retrospectively analyzed data from 56 Japanese patients with XHIM, including 29 patients who received HSCT. Results The long-term survival rate was poor in those not undergoing HSCT (overall survival rate at 40 years of age, 28.2%). The overall survival rate of patients undergoing HSCT (n = 29) was significantly higher than that of those not undergoing HSCT (n = 27, P = .0231). Moreover, event-free and disease-free survival rates were significantly greater in patients 5 years old or younger at the time of transplantation (n = 14) than in older patients (n = 15). Conclusion On the basis of these results, we concluded that HSCT improved the outcomes of patients with XHIM and that an age of 5 years or younger was optimal for the timing of HSCT because persistent infections and severe organ damage were frequently observed in patients older than 6 years.
Acute erythroid leukemia (AEL) is a high-risk leukemia of poorly understood genetic basis, with controversy regarding diagnosis in the spectrum of myelodysplasia and myeloid leukemia. We compared ...genomic features of 159 childhood and adult AEL cases with non-AEL myeloid disorders and defined five age-related subgroups with distinct transcriptional profiles: adult, TP53 mutated; NPM1 mutated; KMT2A mutated/rearranged; adult, DDX41 mutated; and pediatric, NUP98 rearranged. Genomic features influenced outcome, with NPM1 mutations and HOXB9 overexpression being associated with a favorable prognosis and TP53, FLT3 or RB1 alterations associated with poor survival. Targetable signaling mutations were present in 45% of cases and included recurrent mutations of ALK and NTRK1, the latter of which drives erythroid leukemogenesis sensitive to TRK inhibition. This genomic landscape of AEL provides the framework for accurate diagnosis and risk stratification of this disease, and the rationale for testing targeted therapies in this high-risk leukemia.
The Ewing sarcoma breakpoint region 1 (EWSR1) gene is known to fuse with various partner genes to promote the development of the Ewing sarcoma family of tumors and other sarcomas. In contrast, the ...association of EWSR1 chimeric fusion genes with leukemia has rarely been reported. We identified a novel EWSR1‐associated chimeric fusion gene in a patient with acute myeloid leukemia harboring 46, XY, t (11; 22) (p13; q12) karyotype abnormality. The patient was refractory to intensified chemotherapy including hematopoietic stem cell transplantation. Total RNA paired‐end sequencing identified a novel chimeric fusion gene as EWSR1/ELF5, a member of the E26 transformation‐specific transcription factor family. Transduction of EWSR1/ELF5 to NIH3T3 cells induced transformation by attenuating with the p53/p21‐dependent pathway. The injection of EWSR1/ELF5‐transduced NIH3T3 cells into NSG‐SCID mice systematically induced the development of tumors in vivo. These results revealed the oncogenic potency of EWSR1/ELF5.
Novel chimeric fusion gene, EWSR1/ELF5, was identified in a patient with acute myeloid leukemia (AML). EWSR1/ELF5 induced cetllular transformation by attenuating with the p53/p21‐dependent pathway.
Vedolizumab, an immunosuppressive drug that acts locally on the gastrointestinal tract, is mainly used for the treatment of inflammatory bowel disease, and has been reported to be effective against ...gastrointestinal acute graft-versus-host disease (GI-aGVHD) in adults. However, there is insufficient evidence for pediatric GI-aGVHD. We used vedolizumab to treat three cases of GI-aGVHD in patients aged 1.5–4.4 years. It was significantly effective in two patients and did not cause serious side effects in any patient. Vedolizumab might be effective and safe for pediatric GI-aGVHD refractory to other treatments, but this must be confirmed in future studies.
Antiseizure prophylaxis is required during busulfan administration for hematopoietic stem cell transplantation. However, antiseizure agents such as benzodiazepines and phenytoin may produce adverse ...effects through interaction with other drugs. We retrospectively assessed the prophylactic efficacy and safety of levetiracetam and clonazepam against busulfan-induced seizures between 2013 and 2018. Thirty patients (after 2015) received levetiracetam, and 13 patients (before 2015) received clonazepam in this study. Levetiracetam was well-tolerated and had a significantly lower frequency of adverse effects, such as somnolence, compared with clonazepam, although two patients in the levetiracetam group experienced seizures. Levetiracetam is a feasible option for preventing busulfan-induced seizures.
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