Pharmacotherapeutic advances for chronic myelogenous leukemia: beyond tyrosine kinase inhibitors

ABSTRACT

Introduction

Despite the notable success of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML), a subset of patients experiences resistance, or relapse after discontinuation. This challenge is attributed to the Ph+ leukemia stem cells (LSCs) pool not fully involved in the inhibition process due to the current therapeutic approach.

Areas covered

Current pharmacological advancements in CML therapy focus on targeting LSCs, intervening in self-renewal pathways, and exploiting biological vulnerabilities. Beyond BCR::ABL1 inhibition, innovative approaches include immunotherapy, epigenetic modulation, and interference with microenvironmental mechanisms.

Expert opinion

Diverse therapeutic strategies beyond TKIs are under investigation. Immunotherapy with interferon-α (IFN-α) shows some biological effects, although further research is needed for optimal application in enhancing discontinuation rates. Other compounds were able to mobilize Ph+ LSCs from the bone marrow niche (DPP-IV inhibitor vildagliptin or PAI-1 inhibitor TM5614) increasing the LSC clearance or target the CD26, a Ph+ specific surface receptor. It is noteworthy that the majority of these alternative strategies still incorporate TKIs. In conclusion, novel therapeutic perspectives are emerging for CML, holding the potential for substantial advancements in disease treatment.

KEYWORDS:

• Chronic myeloid leukemia
• treatment-free remission
• leukemia stem cells
• immunotherapy
• mobilization
• epigenetic
• strategies

Article highlights

• Leukemia Stem Cells (LSCs) persistently drive treatment resistance and relapse in CML, surviving TKI therapy. Several possible targets have been identified including surface markers, dysregulated signaling pathways, the bone marrow microenvironment, immune system, and epigenetic regulation.

• Interferon-α (IFN-α) has garnered renewed interest in enhancing treatment-free remission (TFR) rates. Clinical trials such as DASA-PegIFN and PETALs exploring TKI combination with Peg-IFN-α but reported conflicting outcomes. The ENDURE-CML-IX study with ropeg-IFN failed to increase the rate of patients who at least maintain a molecular response.

• Nanomedicine represents a potentially groundbreaking development in oncological treatments, including leukemia, enhancing drug effectiveness while minimizing toxicity. A notable example involves the anti-CD26 monoclonal antibody begelomab conjugated with an immunoliposome loaded with the BCL-2 inhibitor venetoclax, demonstrating exceptional selectivity in targeting CD26⁺ CML LSCs.

• Epigenetic modulation has been explored, with chidamide, among HDAC inhibitors, overcoming BCR::ABL1 resistance through the promotion of autophagy. However, these approaches are currently in the preclinical stage and require further evaluation.

Declaration of interest

M Breccia received honoraria by Novartis, Incyte, BMS/Celgene, Pfizer, AbbVie. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.