Targeted Therapy in Acute Lymphoblastic Leukaemia

Abstract

The last decade has seen a significant leap in our understanding of the wide range of genetic lesions underpinning acute lymphoblastic leukaemia (ALL). Next generation sequencing has led to the identification of driver mutations with significant implications on prognosis and has defined entities such as BCR-ABL-like ALL, where targeted therapies such as tyrosine kinase inhibitors (TKIs) and JAK inhibitors may play a role in its treatment. In Philadelphia positive ALL, the introduction of TKIs into frontline treatment regimens has already transformed patient outcomes. In B-ALL, agents targeting surface receptors CD19, CD20 and CD22, including monoclonal antibodies, bispecific T cell engagers, antibody drug conjugates and chimeric antigen receptor (CAR) T cells, have shown significant activity but come with unique toxicities and have implications for how treatment is sequenced. Advances in T-ALL have lagged behind those seen in B-ALL. However, agents such as nelarabine, bortezomib and CAR T cell therapy targeting T cell antigens have been examined with promising results seen. As our understanding of disease biology in ALL grows, as does our ability to target pathways such as apoptosis, through BH3 mimetics, chemokines and epigenetic regulators. This review aims to highlight a range of available and emerging targeted therapeutics in ALL, to explore their mechanisms of action and to discuss the current evidence for their use.

Ferroptosis-related gene signatures in neuroblastoma associated with prognosis

“…According to our drug sensitivity analyses, ATP6V1G2 is associated with nelarabine, a type of drug targeting T-cell antigens ( Salvaris and Fedele, 2021 ), methylprednisolone, which can improve the opsoclonus myoclonus syndrome associated with NB ( Zhu et al, 2021 ), and sapacitabine, a nucleoside analogue inducing DNA strand breaks ( Liu et al, 2012 ), which has been reported to play a role in the treatment of advanced solid ( Denlinger et al, 2021 ) tumor. EPAS1 is sensitive to the multi-tyrosine kinase inhibitor telatinib ( van et al, 2018 ), the Wnt signaling pathway antagonist XAV-939 ( Wang et al, 2021 ), and the dual PI3K/mTOR inhibitor LY3023414 ( Chen et al, 2021 ).…”

The Use of Inhibitors of Tyrosine Kinase in Paediatric Haemato-Oncology—When and Why?

“…It seems quite likely that in the not-so-distant future, paediatric malignancies will be managed via a chemotherapy-free targeted treatment approach [ 152 ]. Research continues to shed light on the potential role of a STAMP inhibitor, and there are currently clinical trials using asciminib in Ph+ ALL and other BCRL/ABL1 fusion-dependent malignancies [ 153 ].…”

Targeted Therapy in Leukaemia, Lymphoma and Myeloma

“…This Special Issue of the Journal of Personalized Medicine entitled "Targeted therapy in Leukaemia, Lymphoma and Myeloma" contains 10 publications authored by experts working in a diverse range of haematological cancers including B cell non-Hodgkin lymphoma [22][23][24][25], T-cell non-Hodgkin lymphoma [26], Multiple Myeloma [27][28][29], Chronic Lymphocytic Leukaemia [23,25,28], Acute Myeloid Leukaemia [28,30] and Acute Lymphoblastic Leukemia [31].…”

“…These neoplasms are biologically distinct but share biological features which enable certain agents to be used across a broad range of tumours including BCL2 inhibitors in B cell non-Hodgkin lymphoma, Multiple Myeloma, Chronic Lymphocytic Leukaemia, Acute Myeloid Leukaemia [28,30]; hypomethylating agents in T cell Lymphoma and Acute Myeloid Leukaemia [26,30]; BTK inhibitors in Chronic Lymphocytic Leukaemia and B cell lymphoma [25]; Cereblon-Interacting Small Molecules in Follicular Lymphoma and Myeloma [22,27,29]; and Bispecific antibodies in B cell lymphoma and B Lymphoblastic leukaemia [24,31].…”

“…Use of monoclonal antibodies and their derivatives is a common theme across the spectrum of blood cancers with bare antibodies, antibody-drug conjugates and bispecific antibodies being active in Acute Myeloid and Lymphoblastic Leukaemia, B-cell and T-cell Lymphoma and Myeloma [22,24,26,[29][30][31].…”