Abstract
Recent studies revealed that a substantial proportion of patients with high-risk B-cell precursor acute lymphoblastic leukemia (BCP-ALL) harbor fusions involving tyrosine kinase and cytokine receptors, such as ABL1, PDGFRB, JAK2 and CRLF2, which are targeted by tyrosine kinase inhibitors (TKIs). In the present study, transcriptome analysis or multiplex reverse transcriptase–PCR analysis of 373 BCP-ALL patients without recurrent genetic abnormalities identified 29 patients with kinase fusions. Clinically, male predominance (male/female: 22/7), older age at onset (mean age at onset: 8.8 years) and a high white blood cell count at diagnosis (mean: 94 200/μl) reflected the predominance of National Cancer Institute high-risk (NCI-HR) patients (NCI-standard risk/HR: 8/21). Genetic analysis identified three patients with ABL1 rearrangements, eight with PDGFRB rearrangements, two with JAK2 rearrangements, three with IgH-EPOR and one with NCOR1-LYN. Of the 14 patients with CRLF2 rearrangements, two harbored IgH-EPOR and PDGFRB rearrangements. IKZF1 deletion was present in 16 of the 22 patients. The 5-year event-free and overall survival rates were 48.6±9.7% and 73.5±8.6%, respectively. The outcome was not satisfactory without sophisticated minimal residual disease-based stratification. Furthermore, the efficacy of TKIs combined with conventional chemotherapy without allogeneic hematopoietic stem cell transplantation in this cohort should be determined.
Highlights
Modern therapeutic strategy of pediatric acute lymphoblastic leukemia (ALL), such as minimal residual disease-based riskadopted treatment, progress of chemotherapy, supportive care and allogeneic hematopoietic stem cell transplantation greatly improved the prognosis of pediatric ALL.[1]
MRNA-seq or multiplex reverse transcriptase–PCR (mRT-PCR) analyses were performed in 373 B-cell precursor ALL (BCP-ALL) patients with sufficient RNA samples. mRNA-seq was performed in 92 patients in the TCCSG cohort and 17 patients in the Japan Association of Childhood Leukemia Study Group (JACLS) cohort according to previously described methods.[16]
Clinical characteristics were not significantly different between the analyzed and non-analyzed groups in TCCSG, Cancer and Leukemia Study Group (CCLSG) and Kyushu–Yamaguchi Childhood Cancer Study Group (KYCCSG) cohorts, National Cancer Institute high-risk (NCI-high risk (HR)) patients were more in the analyzed group in the JACLS cohort
Summary
Modern therapeutic strategy of pediatric acute lymphoblastic leukemia (ALL), such as minimal residual disease-based riskadopted treatment, progress of chemotherapy, supportive care and allogeneic hematopoietic stem cell transplantation (allo-HSCT) greatly improved the prognosis of pediatric ALL.[1]. A number of chimeric fusions, including those involving tyrosine kinase and cytokine receptors, were identified in a subgroup of BCP-ALL designated as Ph-/BCR-ABL-like ALL.[6,7] Because some of these genetic alterations may be treated by molecular targeted therapies, these patients may benefit from specific kinase inhibitor treatment.[8,9] a comprehensive analysis of the clinical characteristics of patients with these kinase fusions is necessary, despite recent reports providing clinical information on these patients.[7,10] The present study aimed to clarify the clinical characteristics of Philadelphia-negative BCP-ALL patients with kinase fusions in Japan by performing a genetic analysis of pediatric BCP-ALL to identify patients with kinase fusions.
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