Clinical impact of minimal residual disease and genetic subtypes on the prognosis of childhood acute lymphoblastic leukemia

• Published in: Cancer 2023-03, Vol.129 (5), p.790-802
• Main Authors: Yu, Chih‐Hsiang, Jou, Shiann‐Tarng, Su, Ying‐Hui, Coustan‐Smith, Elane, Wu, Gang, Cheng, Chao‐Neng, Lu, Meng‐Yao, Lin, Kai‐Hsin, Wu, Kang‐Hsi, Chen, Shu‐Huey, Huang, Fang‐Liang, Chang, Hsiu‐Hao, Wang, Jinn‐Li, Yen, Hsiu‐Ju, Li, Meng‐Ju, Chou, Shu‐Wei, Ho, Wan‐Ling, Liu, Yen‐Lin, Chang, Chia‐Ching, Lin, Ze‐Shiang, Lin, Chien‐Yu, Chen, Hsuan‐Yu, Ni, Yu‐Ling, Lin, Dong‐Tsamn, Lin, Shu‐Wha, Yang, Jun J., Ni, Yen‐Hsuan, Pui, Ching‐Hon, Yu, Sung‐Liang, Yang, Yung‐Li
• Format: Article
• Language: English
• Subjects: Acute lymphoblastic leukemia; Chemotherapy; chemotherapy regimen; Child; Childhood; childhood acute lymphoblastic leukemia; Children; Clinical trials; Dasatinib - therapeutic use; Flow cytometry; Gene sequencing; genetic subtypes; Genomic analysis; Humans; Leukemia; Lymphatic leukemia; Medical prognosis; Minimal residual disease; Neoplasm, Residual - diagnosis; Neoplasm, Residual - genetics; Oncology; Patients; Pediatrics; Polymerase chain reaction; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Prognosis; Remission; Remission Induction; Risk analysis; RNA probes; RNA-directed DNA polymerase; Runx1 protein; Survival; Taiwan Pediatric Oncology Group
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.34606

Background This study analyzed data from two consecutive protocols for children newly diagnosed with acute lymphoblastic leukemia (ALL) to determine the clinical impact of minimal/measurable residual disease (MRD) and recently identified tumor genetic subtypes. Methods Genetic subtypes were determined by sequential approaches including DNA indexing, reverse transcriptase–polymerase chain reaction, multiplex ligation‐dependent probe amplification, and RNA‐sequencing. MRD was assessed by flow cytometry. The Taiwan Pediatric Oncology Group TPOG‐ALL‐2013 study enrolled patients who received MRD‐directed therapy. Results The 5‐year event‐free survival (EFS) and overall survival rates in the 2013 cohort were 77.8% and 86.9% compared to those of the 2002 cohort, which were 62.4% and 76.5%. Among patients treated with MRD‐guided therapy, those with ETV6‐RUNX1 fusion and high hyperdiploidy had the highest 5‐year EFS (91.4% and 89.6%, respectively). The addition of dasatinib improved outcomes in patients with BCR‐ABL1 ALL. Recently identified subtypes like DUX4‐rearranged, ZNF384‐rearranged, MEF2D‐rearranged, and PAX5alt subtypes were frequently positive for MRD after remission induction, and these patients consequently received intensified chemotherapy. Treatment intensification according to the MRD improved the outcomes of patients presenting DUX4 rearrangements. In high‐risk or very‐high‐risk subtypes, the TPOG‐ALL‐2013 regimen did not confer significant improvements compared to TPOG‐ALL‐2002, and the outcomes of BCR‐ABL1‐like, MEF2D‐rearranged, and KMT2A‐rearranged ALL subtypes (in addition to those of T‐cell ALL) were not sufficiently good. Novel agents or approaches are needed to improve the outcomes for these patients. Conclusions The TPOG‐ALL‐2013 study yielded outcomes superior to those of patients treated in the preceding TPOG‐ALL‐2002 study. This study provides important data to inform the design of future clinical trials in Taiwan. Plain language summary MRD‐directed therapy improved the outcomes for pediatric ALL, especially standard‐risk patients. Genomic analyses and MRD might be used together for risk‐directed therapy of childhood ALL. Our work provides important data to inform the design of future clinical trials in Taiwan Genomic analyses and minimal/measurable residual disease together might be the best fit for risk‐directed therapy of childhood acute lymphoblastic leukemia to improve outcomes.