There are actually several subtypes of acute lymphoblastic leukemia (ALL), some of which are especially difficult to manage. The high risk ALL subtypes included in this overview are neonatal ALL, KMT2A rearrangement, Philadelphia chromosome-positive (Ph+), Philadelphia-like (Ph-like), and Early T-cell precursor (ETP).

Ph+ ALL: Tyrosine kinase inhibitors (TKIs), such as imatinib, dasatinib, and nilotinib, constitute a part of the the main treatment for Ph+ ALL, which is characterized by the BCR-ABL1 fusion gene. Chemotherapy and/or steroids are frequently utilized in combination with TKIs. ABL001 provides a new method of ABL inhibition, although ponatinib works well against T315I mutations.

Ph-like ALL: This type of ALL frequently contains CRLF2 rearrangements and ABL-class fusions, but it lacks the BCR-ABL1 fusion yet shares a comparable gene expression profile.(Jain & Abraham, 2020) For CRLF2-rearranged cases, JAK inhibitors like as ruxolitinib show promise, although conventional TKIs might work well for ABL-class fusions.

KMT2A Rearranged ALL: KMT2A rearrangements are frequent in infant ALL and have an undesirable prognosis. (Richard-Carpentier vd., 2021)By targeting protein interactions and epigenetic changes, DOT1L and menin inhibitors,(Candoni & Coppola, 2024) such as SNDX-5613, are becoming potential therapeutic options.

ETP ALL: A rare and aggressive type of T-cell ALL, ETP ALL can be identified by certain genetic changes and immunophenotypic markers.(Onishi vd., 2023) JAK inhibitors and Venetoclax, a BCL-2 inhibitor, are being studied as potential therapies for the dysregulated IL-7 and BCL-2 receptor pathways.

Infant ALL: Challenges with infant ALL include an underdeveloped immune system and high frequency of KMT2A rearrangements. To improve those results, epigenetic modifiers and improved immunotherapeutic strategies, such as CAR T-cell therapy, are being researched.

To sum it up, understanding the particular characteristics each high-risk ALL subtype is critical to designing personalised treatments. To overcome the difficulties presented by drug resistance and immune system infancy, ongoing research and clinical trials are important.