Treating CML: Combination Therapies, TKI Efficacy, Achieving Treatment-free Remission

In an article published in Cells, authors reviewed the chronic myeloid leukemia (CML) treatment landscape, emphasizing the efficacy of tyrosine kinase inhibitors (TKIs) and current therapeutic trends.

The Advent of Tyrosine Kinase Inhibitors

The advent of the TKI imatinib mesylate “revolutionized” CML treatment, with 10-year follow-up data showing that 83% of patients showed complete cytogenetic response, researchers wrote.

However, this targeted therapy was complicated by primary and secondary BCR-ABL1-dependent and -independent resistance to imatinib, leading to the advent of improved TKIs. These included nilotinib, dasatinib, and bosutinib, as well as third line ponatinib, which targets BCR-ABL1 and compound mutations, and asciminib, which functions by binding to a different part of the molecule.

New Territory: Achieving Treatment-free Remission

The previous recommendation was to continue lifelong treatment with TKIs, but due to high costs and adverse events, doctors are now seeking to discontinue therapies and achieve treatment-free remission (TFR).

“Considering the profound knowledge of CML, which has accumulated over the years, the concept of TFR is relatively new, and little is known about the molecular components regulating TFR,” researchers noted.

Current literature in this area is aimed at understanding the impact of type of BCR-ABL1 transcript; number of natural killer cells, B cells, and T cells; and combination of TKIs with interferon alfa and subsequent interferon alfa as maintenance therapy.

“The discovered contributions of the immune system to TFR highlight the importance and still largely unknown role of the immunological microenvironment in the bone marrow and other organs for CML and, probably, other hematological malignancies,” authors concluded.

“With the increasing discovery of the involvement of further molecules and pathways, we believe the scientific community will—at some point—be able to achieve TFR in our patient population and, finally, target and eradicate CML once and for all.”

Reference:
Minciacchi VR, Kumar R, Krause DS. Chronic myeloid leukemia: A model disease of the past, present and future. Cells. 2021 Jan; 10(1):117. doi:10.3390/cells10010117