Precision medicine in acute lymphoblastic leukemia
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REVIEW
Precision medicine in acute lymphoblastic leukemia Ching-Hon Pui (
✉)
Departments of Oncology and Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
© The Author(s) 2020. This article is published with open access at link.springer.com and journal.hep.com.cn 2020
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 immunoand 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, KMT2Arearranged, 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. Keywords acute lymphoblastic leukemia; molecular therapeutics; targeted therapy; tyrosine kinase inhibitors; immunotherapy; CAR T-cell therapy
Introduction Contemporary risk-directed treatment has improved 5-year event-free survival and overall survival rates in childhood acute lymphoblastic leukemia (ALL) to over 80% and 90%, respectively, and has decreased the cumulative risk of relapse to less than 10% in many clinical trials (Table 1) [1–11]. In a recently completed St. Jude Total Therapy Study 16, the 5-year event-free survival rate was 88.2% and the 5-year cumulative risk of any relapse 6.6% among 598 evaluable patients [9] (Fig. 1). Despite the significant reduction of cumulative risk for a CNS relapse or any relapse and a corresponding increase in event-free survival, the overall survival rate (94.1%) in the Study 16 was similar to that (93.5%) in the Study 15 [11]. This outcome suggests that the intensity of conventional chemotherapy has reached its limit of tolerance and can no longer be “pushed” to obtain improved results. Thus, if we intend to
Received October 20, 2019; accepted February 14, 2020 Correspondence: Ching-Hon Pui, [email protected]
boost cure rates and the quality of life of children with ALL in the coming decade, it will be important to replace
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