Advances in the Diagnosis and Treatment of Pediatric Acute Lymphoblastic Leukemia

Abstract

The outcomes of pediatric acute lymphoblastic leukemia (ALL) have improved remarkably during the last five decades. Such improvements were made possible by the incorporation of new diagnostic technologies, the effective administration of conventional chemotherapeutic agents, and the provision of better supportive care. With the 5-year survival rates now exceeding 90% in high-income countries, the goal for the next decade is to improve survival further toward 100% and to minimize treatment-related adverse effects. Based on genome-wide analyses, especially RNA-sequencing analyses, ALL can be classified into more than 20 B-lineage subtypes and more than 10 T-lineage subtypes with prognostic and therapeutic implications. Response to treatment is another critical prognostic factor, and detailed analysis of minimal residual disease can detect levels as low as one ALL cell among 1 million total cells. Such detailed analysis can facilitate the rational use of molecular targeted therapy and immunotherapy, which have emerged as new treatment strategies that can replace or reduce the use of conventional chemotherapy.

Targeted Therapy in the Treatment of Pediatric Acute Lymphoblastic Leukemia—Therapy and Toxicity Mechanisms

“…The two most common genetic lesions with favorable treatment outcomes are ETV 6 /RUNX 1 translocation and high hyperdiploidy in B-cell ALL [ 16 ]. Due to their excellent prognosis based on MRD status measured during and at the end of the induction phase, patients with ETV 6 /RUNX 1 translocation or high hyperdiploid ALL can be treated with conventional chemotherapy regimens with a reduced intensity [ 21 , 22 ]. At present, there are no reliable genetic markers that can be used to identify subsets of T-ALL patients that might benefit from reduced-intensity chemotherapy [ 22 , 23 ].…”

“…At present, research studies are focused on determining whether adding bispecific monoclonal antibodies, such as blinatumomab, to TKI treatment may result in a better molecular response. Another genetic aberration with a dismal cure rate is KMT2A -rearranged ALL, which constitutes a potential target for immunotherapy through the use of blinatumomab and CART-T cell therapy [ 21 , 22 ]. Newly identified provisional entity Ph-like acute lymphoblastic leukemia (Ph-like ALL) accounts for approximately 15% of children with HR B-cell ALL and 10% of SR B-cell ALL subgroups, and is associated with a wide gene expression profile, adverse clinical features, and poor therapy outcome.…”

Oncogene-Induced Reprogramming in Acute Lymphoblastic Leukemia: Towards Targeted Therapy of Leukemia-Initiating Cells

“…Defined as the most frequent pediatric cancer, acute lymphoblastic leukemia (ALL) is a multistep disease characterized by the acquisition of diverse genetic alterations that can be classified into more than 20 B-lineage subtypes (B-ALL) and more than 10 T-lineage subtypes (T-ALL). These different oncogenic subgroups are established according to the identity of the first oncogenic event carrying in the leukemic cells [ 17 ]. Chemotherapy is efficient at inducing long-term remission in child but is associated with severe side effects and undesirable consequences, including second malignant neoplasms.…”

Tamoxifen Sensitizes Acute Lymphoblastic Leukemia Cells to Cannabidiol by Targeting Cyclophilin-D and Altering Mitochondrial Ca2+ Homeostasis

“…For 2021, there are more than 5690 new cases and 1600 deaths estimated for ALL in the United States [1]. T-lineage acute lymphoblastic leukemia (T-ALL) is the less common but highly aggressive ALL associated with unresponsiveness to chemotherapy, and poor prognosis with the lowest survival and highest recurrence rate when compared to other leukemic phenotypes [2,3]. In this context, multiple mechanisms of chemoresistance have been identified by which T-ALL survives after therapy, thus contributing to the frequent relapses and subsequent death of patients [4][5][6][7].…”

“…In this context, multiple mechanisms of chemoresistance have been identified by which T-ALL survives after therapy, thus contributing to the frequent relapses and subsequent death of patients [4][5][6][7]. Despite the substantial progress made in antileukemic treatment [3,8,9], new strategies are needed to improve the therapy. There is accumulated evidence that a multitargeted therapy greatly improves the success rate as compared to monotherapies.…”