Imatinib outcomes in chronic myeloid leukemia across diverse health care settings: a systematic review and meta-analysis

To the editor,

Targeting constitutive BCR::ABL1 kinase activity with tyrosine kinase inhibitors (TKIs), beginning with imatinib, has transformed CML management and substantially improved long-term survival [1]. Later-generation TKIs have further expanded frontline treatment options, enabling contemporaneous risk-adapted treatment strategies [2]. Nevertheless, despite sustained efficacy of imatinib in long-term follow-up of trials [3], treatment outcomes in routine practice remain heterogeneous, suggesting influences beyond disease biology and therapeutic effectiveness [4].

As therapeutic goals in CML evolve [5], structural-level determinants such as access to standardized molecular monitoring, timely response assessment, and sustained treatment adherence have become critical yet underrecognized contributors of real-world effectiveness. These factors are often insufficiently captured in clinical trials, in part due to restrictive eligibility criteria and protocol-driven follow-up, limiting the generalizability of trial-derived benchmarks [6, 7]. To address this gap, we conducted a systematic review and meta-analysis evaluating imatinib outcomes in CML across three health care settings: (i) real world data (RWD) studies, reflecting outcomes in clinical practice among unselected populations; (ii) pivotal clinical trials, which establish benchmarks for drug efficacy and safety under controlled conditions; and (iii) specialized care centers, operating within structured protocols. Detailed methods are provided in the Supplementary Appendix.

Twenty studies met inclusion criteria, encompassing 6638 CML patients (Supplementary Results). Baseline demographic and clinical characteristics differed substantially across care settings. Male predominance was observed across all cohorts but was more pronounced in clinical trials and specialized centers (60.0% and 60.3%, respectively) compared with RWD (55.9%; p = 0.0064). Black and Hispanic patients were substantially underrepresented in clinical trials (2.9% and 2.0%, respectively) relative to RWD cohorts (15.7% and 16.6%), whereas Asian patients were overrepresented in clinical trials compared with RWD (21.6% vs. 6.1%) (Fig. 1).

Fig. 1. Study, demographic, and clinical characteristics of patients treated with frontline imatinib across study settings.

Characteristics are shown for real-world data studies (red), clinical trials (dark blue), and specialized centers (light blue). A Number of patients. B Age of patients. C Time from diagnosis to treatment initiation. D Follow-up duration. E Distribution of clinical and demographic variables.

Clinical context at treatment initiation also varied across settings. Time from diagnosis to imatinib initiation was substantially longer in RWD compared with clinical trials and specialized centers (14.3 ± 18.7 vs. 2.5 ± 0.82 and 2.4 ± 1.1 months, respectively; p < 0.0001). Clinical trials enrolled a higher proportion of patients with low Sokal risk (49.6%) compared with RWD (41.7%) and specialized centers (36.4%). Splenomegaly at diagnosis was nearly threefold more frequent in RWD studies than in clinical trials or specialized centers (56.3% vs. 19.9% and 20.2%, p < 0.0001) (Fig. 1).

We next compared treatment response milestones across cohorts. Early molecular response (EMR, BCR::ABL1 ≤ 10% at 3 months) was significantly lower in RWD than in clinical trials (52.8%, 95% CI 32.9–72.3 vs. 57.9%, 95% CI 52.7–63.1). At 12 months, complete cytogenetic response (CCyR) rates were 65.1% (95% CI 58.2–71.7) in RWD, 67.6% (95% CI 63.6–71.5) in clinical trials, and highest in specialized centers (73.4%, 95% CI 40.7–95.8). A similar gradient was observed for major molecular response (MMR; BCR::ABL1 ≤ 0.1%). At 12 months, MMR rates were lowest in RWD (27.9%, 95% CI 14.5–43.7) and higher, with comparable estimates, in clinical trials (35.2%, 95% CI 25.4–46.1) and specialized centers (36.2%, 95% CI 26.2–46.7). By 24 months, these differences become more pronounced, with MMR rates of 33% (95% CI 19.6–47.9) in RWD, 49.3% (95% CI 41.5–57.1) in clinical trials, and 64.3% (95% CI 55.9–72.2) in specialized centers (Fig. 2).

Fig. 2. Pooled proportion estimates of imatinib and treatment discontinuation across health care settings.

A Early molecular response (EMR) at 3 months, complete cytogenetic response (CCyR) at 12 months, and major molecular response (MMR) at 12 and 24 months. B Disease progression to accelerated phase or blast phase (AP/BP) and mortality outcomes, including all-cause and chronic myeloid leukemia (CML) related mortality. C Five-year progression-free survival and five-year overall survival. D Imatinib discontinuation by reason, including lack of efficacy, and/or treatment intolerance.

Progression to accelerated or blast phase occurred at similar rates in RWD and clinical trials (5.5%, 95% CI 2.7–9.3 vs. 5.2%, 95% CI 3.2–7.6), with slightly higher rates observed in specialized centers (6.5%, 95% CI 2.2–12.9). Five-year progression-free survival (PFS) was high across cohorts (87.4% in RWD, 88.6% in clinical trials, and 83.6% in specialized centers). All-cause mortality varied modestly, ranging from 7.7% (95% CI 3.4–14.1) in RWD to 9.4% (95% CI 7.1–11.9) in clinical trials and 11.7% (95% CI 4.9–20.8) in specialized centers. CML-related mortality was low and relatively consistent across settings (2.6%, 95% CI 0.5–6.2; 4.3%, 95% CI 2.4–6.9; and 4.9%, 95% CI 2.9–7.4, respectively). Five-year overall survival remained high across settings (92.1%, 95% CI 89.9–94.4; 91.2%, 95% CI 88.7–93.4; and 85.3%, 95% CI 79.0–90.4) (Fig. 2).

Patterns of imatinib discontinuation due to failure or intolerance differed by care setting. Overall discontinuation was lowest in RWD (29.7%), highest in clinical trials (43.4%), and intermediate in specialized centers (33.1%). Imatinib discontinuation was primarily driven by lack of efficacy (20.3% in RWD, 16.7% in clinical trials, and 21.9% in specialized centers); in contrast, intolerance-related discontinuation was more common in clinical trials (10.1%) than in RWD (5.9%) or specialized centers (4.3%) (Fig. 2).

Several implications for clinical care, research, and health policy emerge from this analysis. First, marked demographic and clinical differences across care settings underscore the influence of structural factors on patient enrollment and outcomes [8, 9]. Clinical trials consistently enrolled younger, lower-risk, and less diverse populations, reflecting ongoing barriers to trial access [6]. Although RWD studies improve generalizability, they are frequently limited by incomplete reporting, whereas specialized centers provide high-quality monitoring within narrower, referral-based populations. Integrative research models that embed real-world cohorts within academic networks, broaden eligibility criteria, and standardize baseline data collection may help balance methodological rigor with population representativeness [8, 10, 11].

Second, variability in molecular responses appears to reflect system-level determinants, including delays in diagnosis, differences in treatment initiation and adherence, and access to standardized molecular monitoring. Specialized centers achieved higher response rates, likely due to structured follow-up and multidisciplinary expertise [12]. Our findings suggest that optimizing CML outcomes depends as much on the organization and quality of care delivery as on therapeutic selection, supporting the value of pragmatic studies that incorporate adherence metrics, diagnostic timelines, and harmonized monitoring standards.

Third, long-term survival outcomes were favorable across all care settings, reaffirming the durable efficacy of imatinib [13]. Interpretation of survival differences across settings was limited by the inconsistent reporting of time-to-event metrics in RWD studies, which frequently did not report hazard ratios, as well as by variable definitions of PFS [7]. The slightly higher prevalence of death and disease progression in clinical trials and specialized centers may be attributable to longer follow-up and more protocol-driven monitoring in these settings.

Lastly, patterns of treatment discontinuation further reflected contextual differences in care delivery [14]. Higher discontinuation rates in clinical trials likely reflect protocol-driven definitions of failure and intolerance, whereas community-based and specialized center cohorts more closely capture clinician judgment and patient preference. Harmonizing discontinuation criteria and systematically capturing reasons for treatment cessation would improve understanding of treatment persistence in routine practice.

Our findings should be interpreted considering some limitations. Substantial heterogeneity in endpoint definitions and follow-up duration contributed to high between-study heterogeneity across meta-analyses. In addition, most RWD studies did not report hazard ratios for time-to-event outcomes, limiting comparative survival analyses. The predominance of studies from high-resource health care settings may also restrict global generalizability.

In conclusion, our findings reaffirm that imatinib remains a cornerstone of CML therapy, delivering durable disease control across diverse clinical settings. However, outcome variability persists in part due to structural, socioeconomic, and methodological factors. Future progress in CML management will depend not only on therapeutic innovation but also on inclusive trial designs, harmonized real-world research standards, and systematic integration of care delivery metrics and patient-reported outcomes. Addressing these dimensions is essential to bridge the gap between controlled efficacy and population-level effectiveness and to ensure equitable delivery of CML care.

Author contributions

MMG designed the study, conducted the literature search, screened articles, extracted data, interpreted the results, and drafted the manuscript. JW assisted with article screening and data extraction and helped revise the manuscript. YRA participated in article screening, data extraction, and manuscript revision. LJ assisted with literature screening, data extraction, and manuscript editing. AOT contributed to the interpretation of findings and critical revision of the manuscript. RS guided the statistical analysis and meta-analysis and contributed to methodological guidance and manuscript revision. KT assisted with data interpretation and critical review of the manuscript. JEC conceived and supervised the study, contributed to study conception and design, interpreted the findings, and critically revised the manuscript. All authors reviewed and approved the final manuscript.

Data availability

The datasets generated and analyzed during the current study are available from the corresponding author (J.E.C.) upon reasonable request.

Competing interests

The authors declare no competing interests.

Supplementary information

The online version contains supplementary material available at 10.1038/s41408-026-01485-z.