In 2024, the field of chronic myeloid leukemia (CML) witnessed significant breakthroughs in research and clinical advancements. From the development of novel therapeutic agents to the optimization of treatment strategies, from studies on treatment discontinuation to deeper explorations into disease mechanisms, these findings have expanded treatment options and brought new hope to patients. As we step into the new year, Hematology Frontier has invited Dr. Qian Jiang from Peking University People's Hospital to review the key research progress in CML over the past year, particularly focusing on breakthrough findings presented at the ASH and EHA Annual Meetings. Additionally, Jiang shares insights from her team’s clinical experience in CML management and offers a perspective on future directions, aiming to provide new insights for clinical practice and long-term patient care strategies.

ATP-Competitive TKIs: Pioneering the Era of Small Molecule Targeted Therapy in CML

Chronic myeloid leukemia (CML) is a malignant hematologic disorder driven by the BCR::ABL fusion protein. The development of tyrosine kinase inhibitors (TKIs) targeting the ATP-binding site of the BCR::ABL1 kinase marked the beginning of small-molecule targeted therapy for CML. Since the approval of the first-generation TKI imatinib in 2001, the field has progressed dramatically with the introduction of second-generation TKIs such as dasatinib, nilotinib, bosutinib, and flumatinib, followed by third-generation agents such as ponatinib and olverembatinib.

A notable advancement in this trajectory was the approval of flumatinib in 2019, a second-generation TKI independently developed in China. The clinical development of flumatinib began well before its market approval, with extensive research supporting its efficacy and safety. A landmark study in this regard was the FESTnd trial, a nationwide, multicenter, randomized, controlled Phase III study led by Jianxiang Wang from the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences. The study compared the efficacy and safety of flumatinib against imatinib in newly diagnosed chronic-phase CML (CML-CP) patients.

The findings demonstrated that flumatinib led to significantly higher rates of major molecular response (MMR), early molecular response (EMR), complete cytogenetic response (CCyR), and deep molecular response (DMR) compared to imatinib. Patients treated with flumatinib achieved responses earlier and more profoundly, reinforcing its clinical value. The success of this trial contributed to flumatinib’s approval, offering newly diagnosed CML patients a more effective treatment option. Beyond improving treatment efficacy, flumatinib also addressed resistance and intolerance issues associated with imatinib, further expanding its role in clinical practice. Over five years since its approval, flumatinib has gained widespread use, with extensive clinical data confirming its efficacy, safety, and tolerability.

To further assess the comparative performance of TKIs in frontline therapy, Jiang’s team collaborated with 76 centers nationwide, collecting data from over 7,000 CML cases. This large-scale analysis evaluated four TKIs available for first-line treatment—flumatinib, imatinib, nilotinib, and dasatinib—focusing on their efficacy and safety profiles. The results revealed that all four TKIs exhibited comparable efficacy, with no significant differences in treatment outcomes among the second-generation agents (nilotinib, dasatinib, and flumatinib). These findings confirm that for newly diagnosed chronic-phase CML patients, second-generation TKIs remain the preferred treatment options, providing more choices for patients, particularly those who exhibit intolerance to earlier-generation therapies.

The introduction of flumatinib marks a major milestone in China’s independent drug development efforts in CML treatment. As a frontline therapy option, it has enriched treatment strategies and provided significant clinical benefits for CML patients in China. Its success also underscores China’s growing capabilities in new drug development and a deep understanding of patient needs.

STAMP Inhibitors: A New Frontier in CML Treatment

Since the advent of ATP-competitive TKIs, the long-term prognosis of CML patients has significantly improved. However, despite these advancements, newly diagnosed CML patients treated with ATP-competitive TKIs still face numerous unmet clinical needs. To address these challenges, researchers have been actively exploring new therapeutic options with superior efficacy and long-term safety, leading to the development of STAMP inhibitors as a promising alternative for CML treatment.

Currently, four STAMP inhibitors are in development: asciminib, TGRX-678, HS-10382, and AS1266. Among them, asciminib stands out as a unique allosteric inhibitor that does not bind to the ATP site but instead targets the myristoyl pocket of BCR-ABL1. This distinct mechanism makes it highly effective against tumors harboring the T315I resistance mutation, suggesting its potential for combination therapy with ATP-site inhibitors to overcome resistance mutations. Based on findings from the Phase III ASCEMBL trial and the Phase I dose-escalation study (NCT02081378), asciminib became the first and only globally approved STAMP inhibitor, indicated for chronic-phase (CP) Philadelphia chromosome-positive CML (Ph+ CML) patients who have received at least two prior TKIs, as well as CP Ph+ CML patients with the T315I mutation.

Following its success in later-line settings, asciminib has now moved into frontline therapy for CML. Recent reports from major international conferences have highlighted its remarkable first-line efficacy, demonstrating superior effectiveness compared to ATP-competitive TKIs such as imatinib, nilotinib, and bosutinib. Unlike ATP-competitive inhibitors, asciminib has minimal off-target effects, leading to a significantly improved safety profile. Clinical trial data show that the rate of treatment discontinuation and dose adjustments due to drug toxicity is much lower in the asciminib group compared to other TKI groups, positioning it as a highly promising first-line therapy for CML.

Recognizing its outstanding efficacy and safety, asciminib’s market approval application was accepted by China’s National Medical Products Administration (NMPA) on June 25, 2024, for first-line CML treatment, with an expected market launch in China within the year. If approved, asciminib will provide Chinese CML patients with a novel and effective treatment option, further enhancing clinical outcomes and improving patient quality of life. As research in this area progresses, asciminib and other emerging agents are anticipated to bring additional breakthroughs, reinforcing the continued evolution of CML therapy.

TGRX-678: A Novel BCR::ABL1 Allosteric Inhibitor from China

At the 66th American Society of Hematology (ASH) Annual Meeting in 2024, Jiang’s team presented an oral abstract (Abstract #477) on the latest findings from the Phase I clinical trial of TGRX-678, a novel allosteric ABL kinase inhibitor developed in China. This agent selectively targets the STAMP domain of ABL’s myristoyl pocket, demonstrating high specificity, strong potency, low off-target effects, and reduced toxicity.

The TGRX-678-1001 trial (NCT05434312) is an open-label Phase Ia/Ib first-in-human study evaluating the safety, preliminary efficacy, and pharmacokinetics of TGRX-678 in chronic-phase (CML-CP) or accelerated-phase (CML-AP) patients with resistance or intolerance (R/I) to prior TKIs. The study enrolled CML patients who exhibited resistance or intolerance to imatinib, dasatinib, or nilotinib, with participants receiving escalating doses of TGRX-678. The initial results revealed acceptable hematologic and non-hematologic adverse event profiles, along with promising efficacy across different patient subgroups. Pharmacokinetic analysis demonstrated dose-proportional exposure and a long terminal half-life, suggesting favorable drug characteristics.

At the upcoming international medical conferences, the team plans to report updated findings from the TGRX-678 trial. While early development has primarily focused on assessing its safety and efficacy, future research will investigate resistance mutation mechanisms, an area that remains a key priority. Given the growing global interest in novel STAMP inhibitors, ongoing studies aim to validate the long-term benefits of TGRX-678, particularly its potential clinical advantages in accelerated-phase CML patients.

To further evaluate the therapeutic potential of TGRX-678, Jiang’s team at Peking University People’s Hospital, in collaboration with more than ten leading medical centers across China, has initiated a Phase II clinical trial (NCT06453902) to assess the drug’s efficacy and safety in diverse CML patient populations. The study is actively enrolling participants, with the goal of providing a novel therapeutic option for CML patients while accumulating valuable real-world data on Chinese patient outcomes.

As a next-generation allosteric inhibitor, TGRX-678 represents a promising solution for patients with resistance to ponatinib or asciminib, offering new hope in overcoming drug-resistant CML. With further clinical advancements, this agent has the potential to become a key player in the future of CML treatment.

Advances in TKI Discontinuation Research for CML

For more than a decade, researchers worldwide have been exploring treatment-free remission (TFR) in CML patients undergoing tyrosine kinase inhibitor (TKI) therapy. Despite numerous studies indicating that approximately 50% of patients can successfully discontinue TKIs and maintain TFR, critical questions remain. The key challenges include improving the success rate of treatment discontinuation and helping more patients achieve the necessary criteria for stopping therapy. These topics remain central to ongoing global research in CML.

At the 2024 ASH Annual Meeting, Jiang’s team, in collaboration with Weiming Li’s team from Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, presented findings from the largest CML TKI discontinuation model in China. By gathering data from 744 CML patients who discontinued TKI therapy between 1999 and 2024 across 11 centers nationwide, the study applied big data and machine learning algorithms to identify key factors influencing TFR success. The analysis found that the duration of deep molecular response (DMR) before discontinuation and genetic fluctuations (defined as two consecutive losses of DMR during treatment) were major predictive factors affecting TFR success.

In addition to discontinuation strategies, Jiang’s team previously presented a study at the 2023 EHA Annual Meeting that evaluated the efficacy of reduced-dose TKI therapy after achieving major molecular response (MMR). This study aimed to identify patients who could benefit from dose reduction, ultimately minimizing adverse effects while preserving therapeutic efficacy. The findings contribute to ongoing efforts to balance effective disease control with improved patient quality of life.

However, withdrawal syndrome following TKI discontinuation remains a concern, affecting approximately one-third of patients and potentially impacting their quality of life. The team analyzed high-risk patient groups for withdrawal syndrome and found that longer treatment duration and older age were significant risk factors. These insights provide a crucial reference for clinicians managing patients before TKI discontinuation. Proper physician-patient communication is essential before stopping therapy. Patients should be fully informed about the potential benefits and risks, including the possibility of withdrawal syndrome within the first year, which may manifest as generalized pain or discomfort. Raising awareness about these potential effects can help improve patient adherence to treatment decisions and mitigate concerns about discontinuation-related symptoms.

Breakthroughs in CML Blast Phase Treatment: Combination Therapy to Restore Chronic Phase

Although CML blast phase (CML-BP) is rare, it remains one of the most challenging stages of the disease, with extremely poor prognosis and no standardized induction regimen capable of fully restoring patients to chronic phase for long-term disease control. Research efforts continue worldwide to address these challenges. Leading medical centers in the UK, the MD Anderson Cancer Center in the US, and multiple institutions in France have conducted studies aimed at optimizing treatment strategies to prolong survival and potentially return advanced-stage patients to chronic phase.

In recent years, CML blast phase treatment has gained increasing attention at international CML-focused sessions. Jiang’s team contributed to these discussions at the 2024 EHA Annual Meeting, presenting a poster study on third-generation TKIs combined with the hypomethylating agent azacitidine for CML-BP treatment. The single-center study explored response rates and biomarkers associated with treatment outcomes. The combination therapy demonstrated a remarkable response rate, with over 70% of patients successfully returning to chronic phase, and showed a favorable safety profile.

For patients who achieved high response rates, some were able to undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT) as a consolidation strategy to extend survival. Those ineligible for transplantation benefited from long-term treatment with this regimen, maintaining disease control. Moreover, the study identified biomarkers that could predict treatment responses, providing valuable insights into personalized therapy selection for CML-BP patients.

These findings enhance the understanding of therapeutic strategies for CML blast phase and deepen knowledge of the disease’s biological characteristics. Jiang’s team is currently exploring more refined combination regimens tailored to blast phase patients, aiming to expand treatment options and improve long-term outcomes.

Conclusion

Reflecting on 2024, significant progress was made in CML research, offering new hope for patients. However, challenges remain, particularly in optimizing treatment discontinuation strategies, overcoming resistance, and improving blast phase management. Looking ahead, continued efforts in basic research and clinical practice will be critical in refining treatment approaches and advancing precision medicine and individualized therapies for CML. With ongoing scientific advancements and novel drug developments, there is growing optimism that CML patients will achieve longer survival, improved quality of life, and, ultimately, long-term disease control or even a cure.