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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

邮发代号 80-967

2019 Impact Factor: 3.421

Frontiers of Medicine  2020, Vol. 14 Issue (6): 689-700   https://doi.org/10.1007/s11684-020-0759-8
  本期目录
Precision medicine in acute lymphoblastic leukemia
Ching-Hon Pui()
Departments of Oncology and Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
 全文: PDF(279 KB)   HTML
Abstract

The cure rate of childhood acute lymphoblastic leukemia (ALL) has exceeded 90% in some contemporary clinical trials. However, the dose intensity of conventional chemotherapy has been pushed to its limit. Further improvement in outcome will need to rely more heavily on molecular therapeutic as well as immuno- and cellular-therapy approaches together with precise risk stratification. Children with ETV6-RUNX1 or hyperdiploid>50 ALL who achieve negative minimal residual disease during early remission induction are suitable candidates for reduction in treatment. Patients with Philadelphia chromosome (Ph)-positive or Ph-like ALL with ABL-class fusion should be treated with dasatinib. BH3 profiling and other preclinical methods have identified several high-risk subtypes, such as hypodiplod, early T-cell precursor, immature T-cell, KMT2A-rearranged, Ph-positive and TCF-HLF-positive ALL, that may respond to BCL-2 inhibitor venetoclax. There are other fusions or mutations that may serve as putative targets, but effective targeted therapy has yet to be established. For other high-risk patients or poor early treatment responders who do not have targetable genetic lesions, current approaches that offer hope include blinatumomab, inotuzumab and CAR-T cell therapy for B-ALL, and daratumumab and nelarabine for T-ALL. With the expanding therapeutic armamentarium, we should start focus on rational combinations of targeted therapy with non-overlapping toxicities.

Key wordsacute lymphoblastic leukemia    molecular therapeutics    targeted therapy    tyrosine kinase inhibitors    immunotherapy    CAR T-cell therapy
收稿日期: 2019-10-20      出版日期: 2020-12-24
Corresponding Author(s): Ching-Hon Pui   
 引用本文:   
. [J]. Frontiers of Medicine, 2020, 14(6): 689-700.
Ching-Hon Pui. Precision medicine in acute lymphoblastic leukemia. Front. Med., 2020, 14(6): 689-700.
 链接本文:  
https://academic.hep.com.cn/fmd/CN/10.1007/s11684-020-0759-8
https://academic.hep.com.cn/fmd/CN/Y2020/V14/I6/689
Fig.1  
Study group Years of study No. of patients Age range (year) T cell ALL (%) 5-year cumulative rate of any relapse (%) 5-year EFS (%) 5-year survival (%) Data source
AIEOP-BFM 2000 2000−2006 4839 1–17 13.2 13.2 81.4±0.6 91.9±0.4 Möricke et al. (2016) [1]
CoALL-07-03 2003−2010 743 1–18 12.9 NA 83±0.3 NA Escherich et al. (2013) [2]
COG 2000−2005 7153 0–22 7 7.2 NA 90.4±0.5 Hunger et al. (2012) [3]
DCOG-10 2004−2011 778 1–18 14.2 8.3 87.0±1.2 91.9±1.0 Pieters et al. (2016) [4]
DFCI 05-001* 2005−2010 697 1–18 0 9.0 86±3 92±2 Vrooman et al. (2018) [5]
EORTC 58951 1998−2008 1947 1–18 15.2 14.7 82.6±0.9 89.7±0.7 Domenech et al. (2014) [6]
MRC UKALL 2003 2003−2011 3126 1–25 12 8.8 87.3±1.4 91.6±1.2 Vora et al. (2014) [7]
NOPHO-2008 2008−2014 1022 1–9 9.1 13 89±1 94±1 Toft et al. (2018) [8]
NOPHO-2008 2008−2014 266 10–17 25.2 7.0 80±3 87±2 Toft et al. (2018) [8]
SJCRH 16 2000−2017 598 0–18 17.4 6.6 88.2±3.3 94.1±2.4 Jeha et al. (2019) [9]
TPOG 1999−2010 152 0–18 7.2 NA 84.2±3.0 90.2±2.4 Liu et al. (2014) [10]
Tab.1  
Subtype Risk group Therapeutic approach
ETV6-RUNX1 Low Reduced dose intensity if MRD <104 during early induction or <105 MRD at the end of induction
High-hyperdiploid Low Reduced dosed intensity if MRD <104 during early induction or <105 MRD at the end of induction
DUX4-rearranged Low Standard dose intensity, MRD-adapted
ETV6-RUNX1-like Standard Standard dose intensity, MRD-adapted
TCF3-PBX1 Standard Standard dose intensity, MRD-adapted, high-dose methotrexate
PAX5 P80R Intermediate Standard dose intensity, MRD-adapted
PAXalt Intermediate Standard dose intensity, MRD-adapted
ZNF384-rearranged Intermediate Standard dose intensity, MRD-adapted
Philadelphia chromosome-positive High ABL tyrosine kinase inhibitors, retinoids, Bcl-2 inhibitors, FAK inhibitors
Philadelphia chromosome-like Variable Second or third generation ABL tyrosine kinase inhibitors, JAK inhibitors, Bcl-2 inhibitors
Hypodiploid High Intensive dose intensity, MRD-adapted, Bcl-2 inhibitors
KMT2A-rearranged High DOTL1i, Menin inhibitors, Bcl-2 inhibitors
TCF-HLF High Intensive dose intensity, Bcl-2 inhibitors
MEF2D-rearranged High Histone deacetylase inhibitors, bortezomib
Early T cell precursor High Intensive dose intensity, Bcl-2 inhibitors
Tab.2  
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