Therapies on the horizon for childhood acute lymphoblastic leukemia

Abstract

Purpose of the review The prognosis for children with the most common childhood malignancy, acute lymphoblastic leukemia (ALL) has improved dramatically. However the burden of therapy can be substantial with long term side effects and certain subgroups continue to have a poor outcome. Recent Advances The recent discovery of new genetic alterations in high risk subsets provide targets for precision medicine-based interventions using existing FDA approved agents. Novel immunotherapeutic approaches are being deployed in relapsed ALL, one of the leading causes of cancer cell death in children. Moreover genomic analysis has charted the evolution of tumor subclones and relapse specific alterations now provide a mechanistic explanation for drug resistance setting the stage for targeted therapy. There is greater recognition that host factors, genetic polymorphisms, influence cancer risk, response to therapy and toxicity. In the future it is anticipated that they will be integrated into clinical decision making to maximize cure and minimize side effects. Recent efforts to limit prophylactic central nervous system irradiation have been successful thereby sparing many children late neurocognitive impairments. Summary Integration of advances in precision medicine approaches and novel agents will continue to increase the cure rate and decrease the burden of therapy for childhood ALL.

Cytogenetics, Molecular Genetics and Epigenetics and Their Impact on The Management of Acute Lymphoblastic Leukemia

“…Nevertheless, novel therapies are needed to improve the outcome of patients with Ph-like ALL as this this subtype of ALL represents a disease where precision medicine testing, and treatment approach should be implemented [90,94,99]. Newly discovered genetic alterations that drive HR Ph-like ALL can now be targeted with TKIs and JAK inhibitors leading to clinical trials for this particular HR subset [100]. Birinapant is a small molecule mimetic of the apoptotic regulator SMAC.…”

“…Multiple studies have shown that, in addition to allogeneic HSCT, the following novel therapies are effective in patients with drug resistant or relapsed ALL: clofarabine, nelarabine, dasatinib alone or in combination with hyper-CVAD, sphingosomal vincristine, pegylated asparaginase, blinatumomab, ponatinib, chimeric antigen receptor (CAR) T-cells, SRC inhibitor KX2-391 in T-cell ALL and the BCL2 inhibitor venetoclax [54,81,86,100,[120][121][122]. The latter drug has been found to be highly effective in pre-B ALL with MLL-AF4 and TCF3-HLF mutations.…”

“…Prospective testing and therapy modifications can be achieved in real time, allowing patients who might have suffered relapse to achieve adequate control for HR ALL [118]. The discovery of relapse-specific genetic mutations provides an explanation for clonal evolution, drug resistance and the possibility of designing therapies to prevent relapse [100]. Risk factors for relapse in ALL include: (1) WBC count > 100 × 10 9 /liter, and (2) having genes that express drug resistance such as: MLL-AF4, TEL-AML1, BCR-ABL and NT5C2 mutations that are associated with resistance to 6-mercaptopurine and 6-thioguanine [52,53].…”

“…It can be used as a single agent or in combination with vincristine or dexamethasone [47]. Novel immunotherapeutic approaches using BiTE antibodies and CAR T-cells offer great promise in treating relapsed disease which is a leading cause of death in patients with ALL [100]. In order to reduce neurophysiological sequelae of radiotherapy, CNS irradiation can be limited to a very small subset of patients at initial diagnosis or even abandoned completely [100].…”

“…Host genetic polymorphisms are associated with: (1) predisposition to childhood ALL, (2) response to therapy, and (3) adverse effects of medications [100]. Prospective testing and therapy modifications can be achieved in real time, allowing patients who might have suffered relapse to achieve adequate control for HR ALL [118].…”