Chronic myeloid leukemia: special scenarios and newer therapies

The treatment landscape for chronic myeloid leukemia (CML) in chronic phase (CML-CP) has undergone remarkable advancements since the introduction of BCR::ABL1 tyrosine kinase inhibitors (TKIs) in the early 2000s. Imatinib, the first TKI approved, significantly improved overall survival (OS) in patients with newly diagnosed CML-CP. Subsequently, second-generation TKIs—dasatinib, nilotinib, and bosutinib—were approved as frontline and salvage therapies for CML-CP. While these agents achieved faster and deeper responses, they did not significantly improve OS compared with imatinib. With TKI therapy, the long-term OS of patients with CML-CP now approaches 95% (1).

Despite these advancements, treatment failure remains a challenge, predominantly due to disease resistance or treatment intolerance. Long-term follow-up studies indicate that TKI intolerance occurs in 15% to 25% of patients after 10 years of therapy, making it the most common cause for treatment changes. Resistance, defined as BCR::ABL1 transcript levels of ≥1% on the International Scale (IS) after at least 12 months of therapy or progression to advanced phases of CML, affects approximately 10% of patients after 10 years (2). Decisions regarding subsequent lines of therapy depend on prior treatments, comorbidities, the presence of ABL1 kinase domain mutations, and drug availability.

Ponatinib, a third-generation TKI, is approved for patients with CML-CP who have failed at least two prior TKIs or harbor the T315I mutation. However, long-term use of ponatinib is associated with cardiovascular adverse events, necessitating dose adjustments or treatment discontinuation (3). Asciminib, a first-in-class inhibitor specifically targeting the ABL1 myristoyl pocket (STAMP), is approved across all lines of therapy, including third-line and beyond, as well as for patients with the T315I mutation (4,5). Nonetheless, some patients eventually experience disease progression despite treatment with ponatinib and/or asciminib. Olverembatinib, a third-generation TKI, is approved in China for adult patients with CML-CP resistant to or intolerant of first- and second-generation TKIs, as well as for those with the T315I mutation (6). A phase II clinical trial in the United States demonstrated robust clinical activity for olverembatinib in heavily pre-treated patients with CML-CP, including those resistant to or intolerant of ponatinib or asciminib (7).

With near-normalization of survival, achieving treatment-free remission (TFR) has emerged as an important therapeutic goal for patients with CML-CP who achieve sustained deep molecular responses (DMR, defined as BCR::ABL1 transcripts ≤0.01% IS) (8). Discontinuing treatment mitigates long-term side effects and financial burdens associated with TKI therapy. Additionally, it offers younger women the opportunity to safely discontinue TKIs, assuming sustained DMR is achieved, to pursue pregnancy.

Dr. Najdi and colleagues provide valuable insights into the management of CML during pregnancy. They review the teratogenic risks associated with each TKI and recommend strategies for TKI use or avoidance during pregnancy. The authors also explore alternative treatment options, including hydroxyurea and interferon, and outline approaches to managing pregnancy in three scenarios: (I) women on therapy who become pregnant; (II) women on therapy planning a pregnancy; and (III) women newly diagnosed with CML during pregnancy.

Dr. Ul Haque and colleagues review the evidence supporting olverembatinib’s role in treating CML-CP among patients failing prior therapies and those with the T315I mutation. Their review begins with an overview of outcomes in patients treated with ponatinib and/or asciminib in salvage settings. They then describe the preclinical development of olverembatinib and summarize early-phase clinical trials conducted in China that led to its approval. Finally, they discuss U.S.-based trials, highlighting the high rates of complete cytogenetic response and major molecular response observed in heavily pre-treated patients, including those who failed ponatinib and/or asciminib.

As Guest Editor, I would like to extend my gratitude to the expert authors for their invaluable contributions to this special series. Their dedication and expertise have enriched this collection, shedding light on advancements in TKI therapy and addressing the unique challenges of managing CML in pregnant patients. We hope this series underscores the ongoing progress in improving outcomes for patients with CML-CP and emphasizes the need for tailored care in specific patient populations, such as pregnant women with CML.

Fadi G. Haddad

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Blood for the series “Chronic Myeloid Leukemia”. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-2024-03/coif). The series “Chronic Myeloid Leukemia” was commissioned by the editorial office without any funding or sponsorship. F.G.H. serves on the advisory board for Sobi and served as the unpaid Guest Editor of the series. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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