Drug clinical trial landscape of chronic myeloid leukemia: achieving the endpoint or continuing the journey?

To the Editor

The management of chronic myeloid leukemia (CML) has undergone substantial advancements over the past 50 years, with tyrosine kinase inhibitors (TKIs), such as imatinib, now firmly established as the primary treatment option due to their remarkable efficacy. Unlike other hematologic malignancies, the majority of CML patients now exhibit a life expectancy on par with that of the healthy elderly population. Nonetheless, a subset of patients with CML experience treatment failure attributable to drug resistance, relapse following drug discontinuation, or disease progression. Additionally, some individuals require multiple lines of TKI therapy, complicating the attainment of sustained remission. Consequently, the development of novel agents targeting a broader spectrum of mutations, the refinement of treatment modalities, and research into patient discontinuation strategies constitute significant areas of interest in the field of CML therapeutics. The substantial rise in clinical trials for CML over recent decades underscores both an increasing interest in this hematologic malignancy and an urgent need for effective therapeutic interventions. However, the pharmacological options presently available for patients with CML in clinics remain limited.

To systematically obtain high-quality data on the progression of CML clinical trials, we conducted a detailed examination of the database available at https://pharma.id.informa.com/. This investigation identified 1,505 clinical trials conducted up to October 2024, providing extensive information on CML nomenclature, therapeutic modalities, treatment regimens, molecular targets, combination therapies, and relevant clinical insights. Following this, a comprehensive analysis was performed to evaluate global trends in CML clinical trial parameters, including quantity, proportionality, typology, and developmental stages.

From 2000 to 2024, the volume of global CML clinical trials has consistently remained elevated, with a marginal decrease in recent years (Fig. 1A). It is evident that a substantial proportion of these trials are phase I and phase II, constituting 24% and 45%, respectively. Only a limited number of trials have advanced to phase III and IV stages (Fig. 1B). Since the advent of the first targeted drug, imatinib, in 2001, targeted therapy has emerged as the preferred treatment to supplant hydroxyurea, interferon, allogeneic hematopoietic stem cell transplantation and other modalities, as evidenced by the proliferation of clinical trials. Nevertheless, challenges such as intolerance or resistance to TKI drugs, relapse post-discontinuation, and uncontrolled disease progression persist; hence there has been a surge in investigations into novel immunotherapies (including vaccines, CAR-T cells etc.) and other therapeutic alternatives (Fig. 1C). Imatinib continues to be the preferred drug for clinical studies. Importantly, researchers are not only investigating the drug’s impact on CML patients, but also conducting comparisons between the original drug and various generics in terms of their side effects, dosage adjustments, and discontinuation. Furthermore, second- and third-generation TKIs are gradually being incorporated into clinical trials with their respective unique advantages, either as monotherapy or in combination regimens for CML patients (Fig. 1D). Promising therapeutic targets for CML have surfaced from early clinical trials, exemplified by BCR-ABL. Presently, BCR-ABL remains the predominant focus, while the remaining targets are predominantly centered around the tyrosine kinase family (Fig. 1E).

Fig. 1

Clinical trial landscape of CML worldwide. A, The number of clinical trials for CML in the past 20 years; B, Clinical phases of CML clinical trials; C, The clinical stages of the primary treatment modalities; D, 9 most commonly used types of therapeutic drugs; E, 18 most common targets for therapeutic drugs; F, Combination partners of CML Treatment. BCR, B-cell receptor; ABL, ABL proto-oncogene 1; KIT, KIT Proto-Oncogene; PDGF, Platelet Derived Growth Factor Receptor; SRC, SRC Proto-Oncogene; LYN, LYN Proto-Oncogene; YES, YES Proto-Oncogene 1; LCK, LCK Proto-Oncogene; FYN, FYN Proto-Oncogene; RRM1, Ribonucleotide Reductase Catalytic Subunit M1; RRM2, Ribonucleotide Reductase Regulatory Subunit M2; FLT, Fms Related Tyrosine Kinase; FGFR, Fibroblast Growth Factor Receptor; TEK, TEK Receptor Tyrosine Kinase; IFNAR, Interferon Alpha And Beta Receptor

Despite the transformative impact of TKIs on disease prognosis, approximately 20–30% of patients exhibit suboptimal initial responses or develop secondary resistance. This resistance arises through various mechanisms [1, 2]. Consequently, the pursuit of combination therapies emerges as an auspicious trajectory. Our investigation unveiled that predominant combinatory therapeutic protocols pivot around successive iterations of TKIs administered concomitantly aimed at mitigating emergence of drug resistance while protracting patient remission intervals (Fig. 1F). Previous investigations have demonstrated in murine models that simultaneous inhibition of BCL-2 and BCR-ABL shows potential for eradicating CML while significantly reducing treatment costs [3]. Consequently, the expected results from a phase II trial assessing Venetoclax in combination with a TKI for CML in 2023 are highly promising. Moreover, there is a pressing need for extensive research into expanding combinatorial therapeutic strategies, aimed not only at improving efficacy but also at enhancing patient survival along with reduction in hospitalization frequency.

Regrettably, there remains a scarcity of CML research focusing on specific demographics, such as adolescents, pregnant individuals, and ethnically diverse populations [4]. Addressing this gap presents a significant future challenge in CML treatment: how to ensure equitable benefits across all population groups? Furthermore, further investigation is warranted through targeted clinical trials tailored to the small cohort of patients in the acute phase of CML, aiming to ascertain optimal treatment modalities for this persistently incurable disease. Nevertheless, existing research data have significantly advanced the precision, standardization, and individualization of CML treatment.

In conclusion, the advancement towards an effective treatment for CML remains a significant challenge. Future progress will necessitate extensive clinical investigations to thoroughly explore this issue. This encompasses not only the concerns of individual patients but also broader societal considerations, such as balancing the substantial costs associated with clinical operations and public funding, as well as the need for expedited regulatory strategies.