Editor’s Note: The treatment of Chronic Myeloid Leukemia (CML) has entered the era of Tyrosine Kinase Inhibitors (TKIs), but the choice of treatment for patients after the failure of first-line therapy remains a focus of clinical attention. Olverembatinib (HQP1351), as the first third-generation TKI independently developed in China, has previously demonstrated excellent efficacy in populations carrying the T315I mutation. However, what is the value of Olverembatinib for patients in the chronic phase (CP-CML) who do not carry the T315I mutation and have developed resistance or intolerance after first-line TKI therapy? At a recent academic conference, Professor Li Weiming from Union Hospital, Tongji Medical College, Huazhong University of Science and Technology shared the latest efficacy and safety data of Olverembatinib in the second-line treatment of CP-CML patients. This article is specially organized for readers.Main Text (Mode B: Academic Depth Interpretation)
Introduction The survival of patients with Chronic Myeloid Leukemia (CML) has been significantly extended since the advent of TKI drugs, but a portion of patients still develop resistance or intolerance during first-line treatment. Especially for patients who do not carry the T315I mutation, options for second-line treatment are diverse, but how to obtain faster and deeper molecular responses remains a core clinical goal. At this conference, Professor Li Weiming from Union Hospital affiliated with Tongji Medical College of HUST provided a deep analysis of the latest clinical research results of Olverembatinib (HQP1351) in the second-line treatment of chronic phase chronic myeloid leukemia (CP-CML), focusing on its efficacy and safety in the non-T315I mutation population.
01 Research Background: In-depth Exploration of Third-generation TKIs into the Second-line Treatment Field
The first-line standard treatment for chronic phase chronic myeloid leukemia (CP-CML) is usually a first-generation (Imatinib) or second-generation TKI (Nilotinib, Dasatinib, Flumatinib). Although the overall prognosis is good, approximately 20%-30% of patients still need to switch drugs due to resistance or severe adverse reactions. As a potent third-generation BCR-ABL1 inhibitor, Olverembatinib not only has a very strong inhibitory effect on wild-type BCR-ABL1 but can also effectively overcome various kinase domain mutations, including T315I. Previous studies have confirmed its significant benefits in third-line treatment and in the T315I mutation population. Based on this, exploring the application prospects of Olverembatinib in second-line treatment, especially for the population without T315I mutations, has important clinical guidance significance.
02 Research Design: A Multi-center, Open-label Second-line Treatment Study
This study is a single-arm, multi-center, open-label clinical trial conducted in China, aimed at evaluating the efficacy and safety of Olverembatinib in second-line treatment of CP-CML patients. • Inclusion Criteria: Adult CP-CML patients; resistant or intolerant to first-line TKIs (such as Imatinib, Nilotinib, Dasatinib, Flumatinib, etc.); BCR-ABL1 kinase domain does not carry the T315I mutation. • Dosing Regimen: Olverembatinib 40 mg, orally administered every other day (QOD), with 28 days as one treatment cycle. • Endpoint Settings: The primary research endpoint is the Major Cytogenetic Response (MCyR) or Complete Cytogenetic Response (CCyR) rate; secondary endpoints include Major Molecular Response (MMR) rate and safety evaluation.
03 Patient Baseline: Resistance Characteristics and Previous Treatment Background
As of the data analysis date, a total of 47 patients were enrolled in the study. The median age of the patients was 42 years, reflecting the trend of younger CML onset in China. The median time from initial diagnosis to the start of Olverembatinib treatment was approximately 1 year. In terms of previous treatment background, the enrolled patients showed high resistance characteristics. About 93% of patients were resistant to first-line TKI treatment, while only a very small number were intolerant. The drugs used in the first line covered all varieties commonly used in clinical practice in China, including Imatinib, Nilotinib, Dasatinib, and the second-generation domestically developed drug Flumatinib. Notably, in genetic mutation testing, about 76% of patients did not detect known BCR-ABL1 kinase domain mutations, further highlighting the potential role of Olverembatinib in dealing with non-mutation-dependent resistance mechanisms.
04 Efficacy Data: High Levels of Cytogenetic and Molecular Remission
Professor Li Weiming presented the latest efficacy analysis of the study as of January this year in the report. The data results are encouraging: • CCyR Rate: Approximately 76% of patients achieved Complete Cytogenetic Response (CCyR), which means the vast majority of patients were able to regain high-quality cellular-level remission after switching to Olverembatinib. • MMR Rate: Approximately 47% of patients achieved Major Molecular Response (MMR). Deep remission at the molecular level is a key indicator for preventing disease progression and improving long-term survival. • Dynamic Remission Trend: The study observed that with the extension of treatment time, the depth of remission with Olverembatinib showed a continuous improvement trend. This means that long-term use of the drug may allow more patients to obtain deeper molecular responses (such as MR4.0 or MR4.5).
05 Subgroup Analysis: Identifying the Most Beneficiary Advantage Populations
To further optimize clinical decision-making, the study conducted subgroup analyses of patients with different characteristics. Preliminary results show:
- Influence of Previous Drugs: Compared to patients who failed first-generation TKIs, those who sequentially received Olverembatinib after failing second-generation TKIs (such as Nilotinib, Dasatinib, Flumatinib) in the first line also showed excellent efficacy. This indicates that Olverembatinib can effectively overcome the challenges brought by resistance to second-generation TKIs.
- Baseline Tumor Burden: Patients with baseline BCR-ABL1 (IS) levels lower than 10% achieved CCyR and MMR at a faster speed and higher proportion after receiving Olverembatinib treatment. This statistical characteristic suggests that early intervention before the patient’s cytogenetic or molecular levels are completely out of control may lead to greater benefits.
06 Safety Evaluation: Overall Controllable, Low Incidence of Cardiovascular Events
Safety is an issue that cannot be ignored in the long-term application of third-generation TKIs. This study detailed the adverse events (AEs) during the treatment period: • Overall Condition: About 90% of patients experienced different degrees of treatment-related adverse events, but the vast majority were grades 1-2. • Grade 3/4 AE: The incidence rate was 45%, mainly manifesting as hematological toxicity, such as neutropenia, thrombocytopenia, and anemia. Professor Li Weiming emphasized that these hematological AEs can be effectively managed in clinical practice through symptomatic supportive treatment or short-term drug suspension or dose reduction. • Serious Adverse Events (SAE): Only 6 patients experienced SAEs related to Olverembatinib, accounting for a very low proportion. • Cardiovascular Safety: Previous third-generation TKIs have often received attention due to vascular embolic events. However, in this study, only 2 cases of possibly related grade 1 hypertension events were observed, and no serious cardiovascular thrombosis or embolic events were observed, with no reports of death during the study period. This reflects the good tolerability of the Olverembatinib 40 mg QOD regimen in second-line treatment.
07 Conclusion and Outlook: A New Standard for Second-line Treatment?
Professor Li Weiming concluded by pointing out that Olverembatinib has shown extremely excellent efficacy in the second-line treatment of CP-CML patients without T315I mutations, with a CCyR rate of 76% and an MMR rate of 47%. This data not only fills the gap for domestically produced third-generation TKIs in the field of second-line treatment but also provides a powerful alternative for patients after the failure of first-line treatment. From a clinical logic perspective, Olverembatinib, with its broader coverage of the BCR-ABL1 kinase domain, can effectively solve the problem of residual clones after first-line treatment. In the future, as the follow-up time extends, we look forward to seeing more long-term data regarding progression-free survival (PFS) and overall survival (OS). Meanwhile, for the precise choice after the failure of second-generation TKIs, Olverembatinib will undoubtedly occupy a pivotal position.
