The efficacy and safety of asciminib treatment in patients with chronic myeloid leukemia as a second-line or beyond second-line treatment: a systematic review and meta-analysis

Abstract

Background:

Patients with chronic myeloid leukemia (CML) are currently experiencing intolerance or lack of efficacy with previous tyrosine kinase inhibitors (TKIs) and benefit from asciminib as a novel TKI.

Objectives:

The purpose of this meta-analysis was to evaluate the efficacy and safety of asciminib as a second-line or beyond second-line treatment for patients with CML.

Design:

A systematic review and meta-analysis.

Data sources and methods:

We searched four databases (PubMed, Cochrane, Web of Science, and EMBASE) for relevant literature from the inception of the databases to February 4, 2024. Two authors independently performed data extraction to assess the efficacy of asciminib using metrics such as the rate of major molecular response (MMR) and the safety of asciminib using the rate of adverse event (AE). We also performed a subgroup analysis based on the reason for starting asciminib. Data were analyzed using either a fixed-effects model or a random-effects model to calculate the rate of MMR and the rate of AEs. We also assessed the quality of the studies by selecting appropriate tools according to the type of included studies.

Results:

We included 8 studies involving a total of 691 patients. The overall MMR rate for patients with CML treated with asciminib was 46.9% (95% CI: 39.8–54.0, p < 0.05). AEs were reported in five studies, with a combined rate of 79.2% (95% CI: 46.6–98.7, p < 0.05) for all grades and 39.5% (95% CI: 17.6–61.3, p < 0.05) for grade ⩾3 AEs. Thrombocytopenia was the most common AE, with a combined rate of 22.5% (95% CI: 18.8–26.3, p < 0.05) for all grades.

Conclusion:

Asciminib is effective in the treatment of patients with CML, and the most common AE during treatment is thrombocytopenia.

Introduction

Chronic myeloid leukemia (CML) is a malignant myeloproliferative neoplasm occurring in hematopoietic stem cells, primarily involving the myeloid lineage, and is defined by patients with myeloproliferative neoplasms carrying the Philadelphia chromosome (Ph).^1–3 The Global Observatory of Cancer Trends (GLOBOCAN) shows that globally, there are an estimated 474,500 cases of leukemia and an estimated 311,600 deaths.^4,5 The annual incidence of CML is 1.0–1.5 cases per 100,000 people, accounting for 15% of all adults with leukemia.^3,6 More people are estimated to be diagnosed with CML in the United States in 2024 than in 2023.^7,8 The Ph chromosome is caused by a reciprocal translocation of DNA between chromosomes 9 and 22, resulting in a gene fusion of the ABL1 gene on chromosome 9 and the BCR gene on chromosome 22, forming the BCR::ABL1 fusion gene, which produces the BCR::ABL1 protein and leads to the development of CML.^1–3,9 The natural course of CML is characterized by the chronic phase (CP), the accelerated phase (AP), and the blast phase (BP), with the majority of patients being in the CP. ¹⁰

Currently, the therapeutic approaches for CML include tyrosine kinase inhibitors (TKIs), interferon alpha, and allogeneic stem cell transplantation, with TKIs being the predominant first- and second-line treatment option.^11,12 TKIs approved for CML include imatinib, dasatinib, nilotinib, bosutinib, and ponatinib. ³ A study has shown that the 5-year overall survival of patients with CML in the United States was less than 50% before the introduction of TKIs, whereas after their introduction, the overall 5-year survival rate increased to more than 80%. ¹³ The emergence of TKIs significantly improved the prognosis of patients with CML, resulting in a near-normal life expectancy. ¹⁴ However, some patients undergoing first-line therapy will experience treatment failure or intolerance and will need to change their medication to switch to second-line therapy. At this point, some patients may show improvement, but there are still patients who remain ineffective after multiple changes in TKIs. This may be due to the development of mutations in BCR::ABL1 fusion gene in some patients. Treatment with ponatinib is recommended when patients enter treatment beyond the second line or become resistant to two or more TKIs. However, due to the cardiovascular toxicity of ponatinib, it cannot be used in patients with pre-existing or concurrent arterial disease. Furthermore, ponatinib needs to be used with caution in patients at risk for cardiovascular events, and the available TKIs do not address their dilemma. ¹¹ To address this problem, asciminib with new targets of action has been developed.

Asciminib inhibits the kinase activity of BCR::ABL1 protein by binding to the myristoyl pocket of ABL1 kinase (specifically targeting the ABL myristoyl pocket (STAMP)), a site distinct from that of the older TKIs, thereby effectively treating patients who do not respond well to or tolerate the previous TKIs.^15–18 A number of clinical trials exist to investigate, among other things, the efficacy of asciminib in the treatment of patients with CML. A randomized controlled study found that asciminib was more effective than bosutinib in CP-CML patients who had received prior treatment with two or more TKIs. ¹⁹ However, the present study extends the study population to all phases of patients with CML. In addition, while some studies have focused on more restricted geographical areas,^20–25 the present study broadened the geographical scope of the patient population.

The purpose of this systematic review and meta-analysis was to identify all studies using asciminib as second-line treatment or beyond for patients with CML, summarize their results, and comprehensively assess its efficacy and safety by expanding the scope of the included study population. We aim to provide reference data on the use of asciminib in patients with CML and to identify its most common adverse events (AEs), thereby alerting clinicians to the importance of preventing such events during the treatment process.

Methods

Study design

This study was conducted in accordance with the PRISMA 2020 statement (Supplemental Material) . ²⁶

Inclusion criteria

(1) Participants: adult patients with all phases of CML treated; (2) Intervention: asciminib monotherapy and asciminib as a second-line or beyond second-line treatment; (3) Controls: treatment with other TKIs or no control group; (4) Outcomes: studies providing a primary outcome that included the major molecular response (MMR) rate, the incidence of all grades of AEs, or the incidence of grade 3 or higher AEs, and/or a secondary outcome that included the complete cytogenetic response (CCyR) rate, MR2 (BCR::ABL1 fusion gene transcript levels ⩽1%) rate, MR4 (BCR::ABL1 fusion gene transcript levels ⩽0.01%) rate, MR4.5 (BCR::ABL1 fusion gene transcript levels ⩽0.0032%) rate, or rates of all AEs; (5) Study design: observational studies, randomized controlled trials (RCTs), non-randomized controlled trials (NRCTs).

Exclusion criteria

(1) Case reports, reviews, letters, editorials, commentaries, basic experiments, experimental registry records, and nonhuman studies; (2) Non-CML patients or those combined with other tumors; (3) Asciminib combined with any other drug or asciminib as the first-line treatment; (4) Studies not including any primary or secondary outcomes; (5) Unavailability of original data; (6) Duplicate publication of results from the same study population.

Ethics approval and consent to participate

This study is a systematic review and meta-analysis. Ethics approval and consent to participate were obtained for the original studies included in this study. This study does not require additional ethics approval and consent to participate.

Data sources and literature search strategy

Two authors (Z.F. and J.X.) independently searched four databases (PubMed, Cochrane, Web of Science, and EMBASE) for relevant literature up to February 4, 2024, using the following keywords: “chronic myeloid leukemia,” “chronic myeloid leukaemia,” “leukemia, myeloid, chronic,” “BCR::ABL1 fusion gene positive,” “asciminib,” “scemblix.” To enhance the literature search, we also searched for citations in published experimental and review articles.

Study selection

Duplicate studies were first removed, followed by screening by two authors (Z.F. and J.X.) who independently reviewed the titles and abstracts. For studies deemed eligible, the full text was obtained and reviewed in the same manner. Disagreements were resolved through discussion, with the third author (W.F.) intervening if necessary.

Data collection process

Data were extracted independently from the included studies by two authors (Z.F. and J.X.) using a predesigned data extraction form. For RCTs with more than two subgroups, data were extracted only for the subgroup receiving asciminib monotherapy. Disagreements were resolved with the help of the third author (W.F.).

Outcomes

We assessed the efficacy of the drugs by MMR rate, MR2 rate, MR4 rate, MR4.5 rate, and CCyR rate, and the safety of the drugs by adverse reaction rate. Primary outcomes included MMR rate, rates of all grades of AEs, and rates of grade 3 or higher AEs. BCR::ABL1 fusion gene transcript levels ⩽0.1% were defined as MMR (MR3). Secondary outcomes included CCyR rate, MR2 rate, MR4 rate, MR4.5 rate, and various AE rates. CCyR was defined as <1% BCR::ABL1 fusion gene-positive nuclei in at least 200 nuclei; MR2 as BCR::ABL1 fusion gene transcript levels ⩽1%; MR4 as BCR::ABL1 fusion gene transcript levels ⩽0.01% or undetectable in cDNAs with >10,000 ABL1 gene transcripts; MR4.5 as BCR::ABL1 fusion gene transcript levels ⩽0.0032% or undetectable in cDNA with >32,000 ABL1 gene transcripts in the same volume used to detect BCR::ABL1 fusion gene ¹¹ ; AEs were graded according to the Common Terminology Criteria for Adverse Events version 4.03 (National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services).

Quality assessment

Risk of bias was assessed using the Risk of Bias 2 (RoB2) tool for RCTs, ²⁷ the Newcastle-Ottawa Scale (NOS) for retrospective studies, and the Methodological Index of Non-Randomized Studies (MINORS) for NRCTs. ²⁸ Two authors (Z.F. and P.S.) independently assessed the included literature, with disagreements resolved by a third author (W.F.) through mutual agreement.

Statistical analysis

Stata 16 (StataCorp LLC) was used for all data analysis. Data was entered into Stata 16 independently by two authors, Z.F. and J.T., and incidence rates and 95% confidence intervals (CIs) were calculated for all dichotomous outcomes. We used Cochrane’s Q test and I² statistic to estimate the heterogeneity of the included studies; a random-effects model was used to estimate the efficacy and safety if I² was ⩾50% or p was <0.05, indicating significant heterogeneity, and a fixed-effects model was used if I² was <50% or p was >0.05, indicating a low level of heterogeneity. We used metaprop for data analysis if the rate of a study was 0% or 100%, otherwise, both used metan for data analysis. We considered the results to be statistically different at p < 0.05. Sensitivity analysis was conducted by excluding one study at a time to assess the statistical significance of the remaining studies. Publication bias was assessed using funnel plots and Egger’s regression asymmetry test. We performed a subgroup analysis based on the reason for starting asciminib, dividing the patients with CML into a group receiving asciminib for resistance to the last prior TKI and a group receiving asciminib for intolerance to the last prior TKI.

Results

Literature search results

A total of 414 articles were retrieved from four databases. After excluding 106 duplicate articles using EndNote 20 software (Clarivate Analytics), we screened the remaining 308 articles by reading the titles and abstracts, leaving 134 articles, which were read in full text, and finally, 8 studies^19–25,29 met the inclusion criteria and were included in this meta-analysis. Figure 1 documents the article screening process in detail.

Figure 1.

Flow diagram of study selection.

Characteristics and qualitative analysis of included studies

A total of eight studies published between 2019 and 2023 were included in this meta-analysis.^19–25,29 Of the included studies, one was a RCT, one was a NRCT, and six were retrospective studies. Studies were conducted in Australia (two), Canada (two), and one each in Germany, the Netherlands, Russia, and Spain. All of these studies used asciminib as second-line or beyond second-line treatment for patients with CML. Median follow-up ranged from 11.2 to 28 months. All studies reported MMR, and five reported the occurrence of different AEs. The specific characteristics of the eight included studies are shown in Tables 1 and 2. We evaluated the quality of the RCTs using the RoB2 tool, the quality of the NRCTs using the MINORS, where single-arm studies were evaluated using only the first eight items, and the quality of retrospective studies was evaluated using the NOS. The results of the quality evaluation are shown in Tables S1 to S3.

Table 1.

Characteristics of included patients and data of indicators to assess efficacy.

author	Hochhaus	Chee	Khadadah	Kockerols	Turkina	Pérez-Lamas	Perusini	Hughes
Year	2023	2022	2023	2023	2021	2023	2023	2019
Country	Germany	Australia	Canada	Netherlands	Russia	Spain	Canada	Australia
Population	CML-CP	CML-CP/AP	CML-CP/AP/BP	CML-CP/AP	CML-CP	CML-CP/AP	CML-CP/AP	CML-CP/AP
References	Hochhaus et al. 19	Chee et al. 20	Khadadah et al. 21	Kockerols et al. 22	Turkina et al. 25	Pérez-Lamas et al. 23	Perusini et al. 24	Hughes et al. 29
Sample	157	20	41	53	32	77	161	150
Patients with the T315I mutation a	NR	NR	7	15	10	4	29	33
Resistant patients/intolerant patients b	95/59	5/11	21/7	23/9	NR	27/47	50/110	43/36
Median age (range), years	52.0 (24–83)	60.1 (20.4–76.9)	60 (17–90)	NR	54 (26–81)	52 (20–87)	53 (40–65)	NR
Female, n (%)	75 (47.8)	6 (30)	23 (56)	23 (43)	19 (59)	38 (49)	77 (48)	66(44)
Median follow-up (range), month	28	NR	12	NR	NR	13.7	11.2 (5.9–20.3)	13.8 (0.02–39)
MMR (time), month	22.4	NR	6	18	NR	14	12	12
MMR (n/N)	59/157	14/20	11/28	23/44	10/29	45/74	74/161	50/118
MR2 (time), month	22.4	7.8	6	18	NR	NR	12	12
MR2 (n/N)	64/142	15/20	15/28	28/44	NR	NR	106/161	76/109
MR4 (time), month	22.4	NR	NR	18	NR	NR	12	12
MR4 (n/N)	27/157	10/20	NR	16/44	5/30	NR	50/161	26/109
MR4.5 (time), month	22.4	NR	NR	NR	NR	14	NR	NR
MR4.5 (n/N)	17/157	NR	NR	NR	NR	23/74	NR	NR
CCyR (time), month	22.4	NR	NR	NR	NA	14	NR	NR
CCyR (n/N)	41/103	NR	NR	NR	8/25	54/74	NR	89/144

^aThe number of patients with the T315I mutation.

^bThe ratio of patients resistant to the last prior TKI to patients intolerant to the last prior TKI.

AP, accelerated phase; BP, blast phase; CCyR, complete cytogenetic response; CML, chronic myelogenous leukemia; CP, chronic phase; MMR, major molecular response (BCR::ABL1 fusion gene transcript levels ⩽0.1%); MR2, BCR::ABL1 fusion gene transcript levels ⩽1%; MR4, BCR::ABL1 fusion gene transcript levels ⩽0.01%; MR4.5, BCR::ABL1 fusion gene transcript levels ⩽0.0032%; n, the number of people who generated the corresponding response; N, total number of participants in the assessment of the corresponding responses; NR, not reported; TKI, tyrosine kinase inhibitor.

Table 2.

Data of indicators to assess safety.

Author	Hochhaus	Chee	Khadadah	Kockerols	Turkina	Pérez-Lamas	Perusini	Hughes
Year	2023	2022	2023	2023	2021	2023	2023	2019
All-grade AEs, n/Nt	142/156	NR	NR	NR	14/32	42/77	NR	150/150
Grade ⩾3 AEs, n/Nt	88/156	NR	NR	NR	7/32	14/77	NR	90/150
References	Hochhaus et al. 19	Chee et al. 20	Khadadah et al. 21	Kockerols et al. 22	Turkina et al. 25	Pérez-Lamas et al. 23	Perusini et al. 24	Hughes et al. 29
All grades of thrombocytopenia, n/Nt	46/156	NR	NR	12/53	5/32	13/77	NR	33/150
Grade ⩾3 thrombocytopenia, n/Nt	35/156	NR	NR	3/53	4/32	3/77	NR	14/150
All grades of neutropenia, n/Nt	36/156	NR	NR	4/53	2/32	5/77	NR	16/150
Grade ⩾3 neutropenia, n/Nt	29/156	NR	NR	1/53	2/32	2/77	NR	11/150
All grades of headache, n/Nt	31/156	NR	NR	NR	NR	1/77	NR	42/150
Grade ⩾3 headache, n/Nt	3/156	NR	NR	NR	NR	0	NR	1/150
All grades of fatigue, n/Nt	23/156	NR	NR	1/53	NR	14/77	NR	44/150
Grade ⩾3 fatigue, n/Nt	1/156	NR	NR	0	NR	2/77	NR	2/150
All grades of arthralgia, n/Nt	20/156	NR	NR	NR	NR	9/77	NR	36/150
Grade ⩾3 arthralgia, n/Nt	1/156	NR	NR	NR	NR	0	NR	2/150
All grades of anemia, n/Nt	16/156	NR	NR	7/53	NR	9/77	NR	17/150
Grade ⩾3 anemia, n/Nt	2/156	NR	NR	2/53	NR	0	NR	11/150

AE, adverse event; n, the number of people who had the AE; NR, not reported; Nt, total number of participants in the assessment of adverse events.

Clinical characteristics of included patients

A total of 691 patients were included in the analysis (Table 1). Of these, 660 patients were diagnosed with CP-CML, 29 with AP-CML, 1 with BP-CML, and 1 with CML of unknown phase. Six studies reported that 19.1% of the included patients harbored the T315I mutation (threonine-isoleucine substitution at position 315).^21–25,29 Seven studies reported that 264 patients received asciminib due to resistance to the last prior TKI, while 279 patients were treated with asciminib due to intolerance to the last prior TKI.^19–24,29 Three hundred twenty-seven patients were female, 363 were male, and the gender of one patient was not reported. The ages of the patients ranged from 17 to 90 years. A total of 35.0% of the patients had received prior treatment with no more than two other TKIs, 63.2% had received prior treatment with no fewer than three other TKIs, and prior use of TKIs was unknown in 12 patients.

Efficacy

In this meta-analysis, we assessed the efficacy of asciminib treatment in all patients with CML based on the primary outcome of MMR rate and the secondary outcomes of MR2 rate, MR4 rate, MR4.5 rate, and CCyR rate. Analysis of the eight included studies using a random-effects model showed that the overall MMR rate for asciminib-treated patients with CML was 46.9% (95% CI: 39.8–54.0, I² = 65.8%; p < 0.05; Figure 2(a)). Analysis of six studies using a random-effects model showed an overall MR2 rate of 61.7% (95% CI: 52.0–71.4, I² = 78.3%, p < 0.05), an overall MR4 rate of 26.7% (95% CI: 19.0–34.5, I² = 72.7%, p < 0.05), and analysis of two studies showed an overall MR4.5 rate of 20.4% (95% CI: 0.6–40.2, I² = 91.4%, p < 0.05). Analysis of four studies showed an overall CCyR rate of 52.6% (95% CI: 35.7–69.5, I² = 90.2%, p < 0.05).

Figure 2.

Forest plots of rate of MMR after treatment (a) and rate of MMR in subgroups of resistant/intolerant (b).

Intolerant, start asciminib for intolerance to the last prior TKI; Resistant, start asciminib for resistance to the last prior TKI; RSA, reason for starting asciminib; TKI, tyrosine kinase inhibitor.

Safety

It included the rate of all grades of AEs and the rate of grade ⩾3 AEs for the primary outcome, as well as the rate of various AEs for secondary outcomes. The composite rate of all grades of AEs was 79.2% (95% CI: 46.6–98.7, I² = 97.8%, p < 0.05; Figure 3(a)), and the composite rate of grade ⩾3 AEs was 39.5% (95% CI: 17.6–61.3, I² = 95.7%, p < 0.05; Figure 3(b)). Of the hematologic AEs, the most common was thrombocytopenia, with an incidence rate of 22.5% (95% CI: 18.8–26.3, I² = 39.1%, p < 0.05), and the incidence rate of grade ⩾3 thrombocytopenia was 10.4% (95% CI: 4.0–16.9, I² = 82.6%, p < 0.05). Anemia had an incidence rate of 11.2% (95% CI: 8.2–14.1, I² = 0.0%, p < 0.05), and grade ⩾3 anemia had an incidence rate of 2.4% (95% CI: 0.1–6.7, I² = 76.5%, p < 0.05). Neutropenia had an incidence rate of 10.9% (95% CI: 4.9–16.8, I² = 77.2%, p < 0.05), and grade ⩾3 neutropenia had an incidence rate of 7.0% (95% CI: 1.8–12.2, I² = 83.8%, p < 0.05). Of the nonhematologic AEs, the most common was headache, with an incidence rate of 14% (95% CI: 2.0–33.0, I² = 97.1%, p < 0.05); the incidence rate for grade ⩾3 headache was 0.8% (95% CI: 0.1–2.2, I² = 0.0%, p < 0.05). Arthralgia followed, with an incidence rate of 16.1% (95% CI: 8.7–23.5, I² = 75.1%, p < 0.05), and the incidence rate for grade ⩾3 arthralgia was 0.6% (95% CI: 0.0–1.9, I² = 0.0%, p < 0.05). Lastly, fatigue was reported at an incidence rate of 15.8% (95% CI: 3.5–28.0, I² = 94.2%, p < 0.05), and grade ⩾3 fatigue at an incidence rate of 1.0% (95% CI: 0.1–1.9, I² = 0.0%, p < 0.05).

Figure 3.

Forest plots of rate of all grades AEs (a) and rate of grade⩾3 AEs (b) after treatment.

AE, adverse event.

Subgroup analysis

We categorized patients with CML into the group receiving asciminib for resistance to the last prior TKI and the group receiving asciminib for intolerance to the last prior TKI. The results (Figure 2(b)) showed that the rate of MMR in the group receiving asciminib for resistance to the last prior TKI was 31.0% (95% CI: 24.4–37.6, I² = 0.0%, p > 0.05), whereas the rate of MMR in the group receiving asciminib for intolerance to the last prior TKI was 66.2% (95% CI: 48.7–83.8, I² = 80.7%, p < 0.05). The overall rate of MMR across all patients in the two groups was 47.9% (95% CI: 31.1–64.8, I² = 91.0%, p < 0.05).

Sensitivity analysis

After performing a sensitivity analysis on the MMR data using the case-by-case method, the results (Figure 4) showed that the incidence rate of MMR was not affected by the results of any individual study, indicating that the findings were stable.

Figure 4.

Sensitivity analysis of MMR.

MMR, major molecular response.

Publication bias

Upon constructing a funnel plot (Figure 5) of the MMR results from the eight included studies, visual inspection revealed no asymmetry. This was further supported by Egger’s test, which yielded a result of p = 0.364, indicating significant symmetry within the funnel plot, which suggests that there was no significant publication bias in the study.

Figure 5.

Funnel plot of MMR.

MMR, major molecular response.

Discussion

This meta-analysis included 8 studies^19–25,29 involving a total of 691 patients to assess the efficacy and AEs of asciminib in patients with CML. The results of this meta-analysis showed that the overall MMR rate in all CML patients was 46.9%. The subgroup analysis suggested that the reason for starting asciminib did not contribute to heterogeneity. In addition, the combined rate of AEs at all grades was 79.2%, and AEs of grade 3 or higher were 39.5%. Thrombocytopenia was identified as both the most common AE and the most common AE of grade 3 or higher. Thrombocytopenia usually occurs during the first week of treatment. If a patient develops severe thrombocytopenia, it may not be possible to give the patient an adequate dose of asciminib for treatment. Therefore, we need to monitor patients closely. Patients who develop thrombocytopenia that interferes with normal therapy should be treated with growth factors and, if necessary, platelet transfusions. ¹¹ This meta-analysis is the first to summarize the available data on asciminib-related therapies and to analyze the efficacy and safety of asciminib in patients with CML as second-line or later treatments.

Asciminib has demonstrated excellent efficacy and safety as a second-line or beyond second-line treatment for patients with CML due to its ability to remain effective in treating patients who have developed resistance and intolerance to previous TKIs. This is attributed to asciminib’s distinct mechanism of action, which differs from previous TKIs. Previous TKIs exert their inhibitory effect on the abnormal kinase activity by binding to the adenosine triphosphate (ATP) site on the BCR::ABL1 protein. However, some patients suffer from a lack of efficacy and intolerance due to mutations in the ATP site, which impair the binding of these TKIs and hinder their inhibitory effects.

Unlike the above TKIs, asciminib effectively inhibits the kinase activity of BCR::ABL1 protein through STAMP. Some CML patients with mutations do not inhibit the kinase activity of BCR::ABL1 protein because of the lack of a myristoylated N-terminus of ABL1 that binds to STAMP. Asciminib mimics the action of the myristoylated N-terminus of ABL1, binding to the STAMP and inducing a negative regulation of ABL1 kinase activity. Since asciminib does not bind to the ATP site, mutations in this site do not affect its inhibitory effect, allowing it to overcome the lack of efficacy and intolerance in some patients.^15–18 A common mutation is the T315I mutation.^15–18 When treating patients harboring the T315I mutation with asciminib, higher doses are required due to their strong drug resistance, which may impact the efficacy of the drug. However, three studies have demonstrated that asciminib also exhibits good efficacy in patients with the T315I mutation.^19,21,29

Nevertheless, there are several limitations to our study. First, this meta-analysis included only one RCT and lacked prospective studies, which may reduce the reliability of the results. More RCTs and prospective studies should be included in the future to increase the quality and reliability of the results. Second, the number of patients included in this review is small. The number of patients exposed to asciminib for the relative duration since its introduction in clinical trials is limited. In the ASC4FIRST trial, Hochhaus et al. compared the efficacy and safety of asciminib with investigator-selected TKIs in newly diagnosed CML patients. They found that asciminib demonstrated superior efficacy and safety. ³⁰ However, as we have also considered, both Hochhaus et al. and Abruzzese, in the related editorial, emphasized the need for longer follow-up to assess the long-term efficacy and safety of asciminib in CML patients. ³¹ Therefore, we hope that clinical trials with larger sample sizes and longer follow-ups can be included in the future to improve the reliability of the results. In the meantime, we hope to identify patient populations with greater efficacy for asciminib and to conduct more in-depth studies in the future. Third, a higher dose of asciminib is required when treating patients harboring the T315I mutation, which may lead to an increased incidence of AEs. However, due to insufficient data, the reliability of conclusions regarding the efficacy and safety of asciminib in these patients is limited. We hope that future studies with sufficient data will further explore the efficacy and safety of high-dose asciminib in patients with the T315I mutation. The data in this meta-analysis were somewhat heterogeneous, with an I² of 65.8% for the total MMR rate, indicating heterogeneity that we believe originated from differences in patient region, age, previous treatment, and asciminib regimen. The I² for all grades of AEs rate was 97.8%, and for grade 3 or higher AEs rate was 95.7%, indicating heterogeneity possibly due to differences in treatment regimens and patient regions. Currently, sufficient data are not available to perform additional subgroup analysis, so the source of heterogeneity could not be verified. We recommend increasing the number of patients included in subgroup analysis and performing more subgroup analyses to fully validate the sources of heterogeneity when data are sufficiently available. Finally, because of the limited follow-up period of the studies included in this meta-analysis, the safety of asciminib could not be adequately clarified and, in particular, the conclusion of long-term adverse events of asciminib could not be substantiated. As Gambacorti-Passerini and Piazza suggested, the median follow-up duration of the ASC4FIRST trial was less than 18 months, which is insufficient to fully assess the safety of asciminib. ³² We expect that more scientifically rigorous clinical studies with sufficiently long follow-up periods will be available in the future. In this way, the safety of asciminib can be further clarified and the occurrence of long-term AEs can be observed. And more credible conclusions can be drawn.

Extended follow-up and collection of results from more patients are needed to further elucidate the efficacy and safety of asciminib. At present, asciminib has demonstrated excellent therapeutic efficacy, and it may have broader application prospects in the treatment of CML, especially for patients who have shown resistance and intolerance to previous TKIs. A study has shown that asciminib, when combined with prior TKIs, also shows excellent therapeutic efficacy. ¹⁷ Thus the emergence of asciminib provides more possibilities for the treatment of CML.

Conclusion

This meta-analysis showed asciminib was effective as second-line or beyond treatment for patients with CML, and the most common AE was thrombocytopenia, which was also the most common grade ⩾3 AEs. It provides guidance for clinicians on the use of asciminib in treating patients with CML. Moreover, it reminds clinicians that they should pay attention to the management of patients after treatment, closely monitor and correctly manage adverse events in a timely manner according to the patient’s condition. They especially need to focus on the early prevention of thrombocytopenia and timely intervention to enhance patient safety during treatment. As envisioned by Hochhaus et al., asciminib has the potential to become a first-line treatment for CML patients in the future. However, before this can be achieved, it is essential to enhance the reliability of the results and further elucidate the long-term efficacy and safety of asciminib. This requires additional studies with larger sample sizes and longer follow-up periods to provide more robust evidence. Additionally, as data on asciminib gradually become more abundant, it will be possible to conduct further analysis of subgroups of CML patients with different characteristics, to identify which types are most suitable for treatment with asciminib.