Abstract
Background
Advanced-phase chronic myeloid leukemia (CML) remains associated with poor outcomes despite advances in tyrosine kinase inhibitor (TKI) therapy, underscoring the need for more effective treatment approaches.
Objectives
This multicenter study evaluated the efficacy and safety of tyrosine kinase inhibitor (TKI) plus azacitidine (with optional low-dose chemotherapy) in advanced-phase CML.
Design
Prospective multicenter single-arm study.
Methods
41 patients with accelerated- (AP) or blast-phase (BP) CML received azacitidine 75 mg/m2/day for 7 days per 28-day cycle (6 cycles) plus TKIs selected by ABL1 mutation status; chemotherapy was added based on early response. Major hematologic response (MaHR) was the primary endpoint. The secondary endpoints included cytogenetic/molecular responses—major cytogenetic response (MCyR), major molecular response (MMR), and undetectable minimal disease (UMD) — along with progression-free survival (PFS) and overall survival (OS). Adverse events (AEs) were documented.
Results
Among 36 evaluable patients (median age 51 years; range: 24-77; AP: 13, BP: 23) after excluding 5 noncompliant patients, 63.9% achieved MaHR, with a median response time of 1.33 months. The cumulative 3-year response rates were as follows: MCyR, 48.5%; MR2.0 (BCR::ABL1 IS ≤1%), 16.3%; MMR, 21.8%; and UMD, 14.2%. Patients maintained sustainable responses during follow-up. Four hematopoietic stem cell transplantation (HSCT) recipients maintained durable remission with TKI consolidation. At 28.1-month median follow-up, median OS was not reached and median PFS was 8.17 months; estimated 3-year OS and PFS rates were 50.3% and 41.1%, respectively. Elevated baseline WBC count and BCR::ABL1 transcript levels predicted poor survival. Hematologic toxicities of grade 3 or higher occurred in 55.6% of patients, including neutropenia (36.1%), thrombocytopenia (33.3%).
Conclusion
TKI–azacitidine therapy demonstrated promising efficacy and acceptable tolerability in patients with advanced-phase CML and may represent a feasible treatment option for this high-risk population.
Keywords: chronic myeloid leukemia, tyrosine kinase inhibitors, azacitidine, DNA methylation, combination therapy
Plain language summary
Chronic myeloid leukemia (CML) is a type of blood cancer caused by a specific genetic abnormality. Most patients can achieve long-term disease control with targeted therapy in the early stages, but some eventually progress to advanced phases (accelerated or blast phase), where the disease progresses rapidly, treatment options are limited, and the prognosis is poor. This study focused on a new combination treatment strategy: adding a gene-expression-modulating drug, azacitidine, to standard targeted therapy. A total of 41 patients with advanced CML were enrolled to evaluate the effectiveness and safety of this combination therapy in a real-world clinical setting, with follow-up up to three years. The results showed that most patients experienced significant hematologic improvement shortly after starting treatment, with about two-thirds achieving effective disease control. In some patients, leukemia cells were also markedly reduced at the chromosomal and molecular levels, suggesting that the therapy not only relieves symptoms but may also suppress deeper disease progression. During follow-up, approximately half of the patients receiving this combination therapy were still alive after three years. For some patients, this treatment successfully provided valuable time to proceed to hematopoietic stem cell transplantation. Regarding safety, treatment-related adverse events were mainly hematologic, most of which could be managed with supportive care, while severe non-hematologic side effects were uncommon. Overall, this study indicates that targeted therapy combined with azacitidine is a relatively safe and effective treatment option, offering new opportunities for patients with advanced CML, particularly as a crucial “bridging therapy” before stem cell transplantation.
Introduction
The development of BCR::ABL1-specific tyrosine kinase inhibitors (TKIs) has redefined chronic myeloid leukemia (CML) management, positioning it as a cornerstone of molecular oncology.1,2 These agents target the Philadelphia chromosome-derived BCR::ABL1 kinase, transforming CML into a manageable chronic condition, with 10-year survival rates surpassing 80% in chronic-phase (CP) patients. 3 Furthermore, 40-50% of individuals attaining sustained deep molecular response (DMR, BCR::ABL1 IS ≤0.01%) can safely discontinue treatment with sustained remission.4–6
Despite these advances, approximately 25% of patients develop resistance or intolerance to TKI therapy, leading to significant disease progression 7 —encompassing patients with accelerated-phase (AP) and blast-phase (BP) CML—characterized by clonal evolution, therapeutic resistance, and dismal outcomes, with median survival <12 months.8–10 Historical data from the pre-TKI era demonstrated universal progression to terminal phases without hematopoietic stem cell transplantation (HSCT), with 5-year survival rates<20%.11–13 While TKI monotherapy reduces progression rates to < 5% in patients with CP-CML, 10 its efficacy in patients with advanced-phase disease remains limited, with <30% of patients with AP-CML or BP-CML achieving durable remission without HSCT.14,15
Challenges in treating patients with advanced-phase CML stem from both genetic heterogeneity and epigenetic dysregulation. In addition to BCR::ABL1-dependent pathways, genome-wide methylation analyses have revealed that hypermethylation of tumor suppressor genes (e.g., CDKN2B and SOCS3) is a critical driver of leukemic stem cell persistence and disease progression. 16 This epigenetic reprogramming provides a rationale for combining TKIs with hypomethylating agents (HMAs) such as azacitidine. Phase II trials of HMA-TKI combinations have demonstrated promising results, including major hematologic response (MaHR) rates of 48-81% and a median overall survival (OS) of 13.8-31.5 months, 17 contrasting favorably with conventional chemotherapy regimens associated with a >60% rate of hematologic toxicities of grade 3 or higher. 18
Current treatment algorithms prioritize HSCT consolidation for eligible patients, yet bridging strategies remain controversial. While intensive chemotherapy combined with TKIs achieves transient responses in 40-70% 8 of patients with BP-CML, its utility is limited by poor tolerability and high relapse rates. Conversely, emerging evidence suggests that HMA-based regimens may enhance molecular responses while maintaining acceptable safety profiles, 19 potentially enabling more patients to bridge successfully to HSCT. 20 However, critical knowledge gaps persist regarding long-term outcomes, optimal HMA-TKI combinations, and predictive biomarkers for response stratification.
To address these unmet needs, we conducted a multicenter prospective cohort study evaluating azacitidine combined with mutation-adapted TKIs ± low-dose chemotherapy in patients with advanced-phase CML. This investigation aimed to (1) quantify hematologic/cytogenetic response durability, (2) identify clinical and molecular predictors of survival, and (3) establish a safety profile of epigenetic-based bridging therapy. Our findings provide new insights into risk-adapted therapeutic approaches for this high-risk population.
In summary, demethylating agents have shown considerable potential for the treatment of CML. Consequently, we conducted a multicenter clinical trial to further investigate the efficacy and safety of demethylating agents (specifically azacitidine) in combination with different TKIs for treating patients with advanced-phase CML. This study aims to provide an alternative treatment option for this patient population.
Methods
Study design and patients
This multicenter prospective cohort study enrolled adults ≥18 years with ELN 2020-defined accelerated-phase (AP-CML) or blast-phase (BP-CML) chronic myeloid leukemia between June 2021 and July 2024. Inclusion criteria were: (1) Eastern Cooperative Oncology Group (ECOG) performance status ≤2; (2) diagnosis of advanced-phase CML: BP-CML (de novo or transformed from chronic phase) or AP-CML arising from chronic phase; (3) no prior hypomethylating agent (HMA, azacitidine/decitabine) exposure and ≥14-day washout for non-TKI therapies (hydroxyurea permitted); (4) adequate organ function. Exclusion criteria were: (1) known hypersensitivity to azacitidine or decitabine; (2) unresolved toxicities from prior therapies (grade >2 according to NCI-CTCAE version 5.0); (3) severe cardiac, hepatic, renal, or psychiatric disorders; (4) uncontrolled active infection, including viral hepatitis, HIV infection, syphilis, or active tuberculosis; (5) prior allogeneic hematopoietic stem cell transplantation; (6) another active malignancy within the previous 3 years, except adequately treated non-melanoma skin cancer, cervical carcinoma in situ, or controlled prostate cancer; (7) de novo AP-CML at initial diagnosis and (8) pregnancy, lactation, or any condition that, in the investigator’s judgment, could compromise patient safety or study participation. The protocol was approved by institutional review boards of all participating centers and registered at the Medical Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology (2020-S348), adhering to the Declaration of Helsinki.
Treatment
This study evaluated the combination of TKIs with azacitidine in patients with advanced-phase CML, with azacitidine administered subcutaneously at 75 mg/m2 per day for 7 consecutive days per 28-day cycle over 6 treatment cycles (minimum of 1 cycle required, with up to 5 additional cycles permitted) (Figure 1). TKI selection was individualized based on each patient’s prior treatments, ABL1 kinase mutation status, comorbidities, and tolerability. Specifically, 1 patient received imatinib with azacitidine, 15 received dasatinib, 15 received flumatinib, 2 received ponatinib, and 3 received olverembatinib, as summarized in Table 1. Each treatment cycle was defined as 28 days. Figure 2 illustrates the overall enrollment and outcomes of patients after each treatment cycle. Due to lack of efficacy after the first treatment cycle, 2 patients with MBP disease received additional low-dose chemotherapy with HHT (2 mg/m2 per day for 7 days), and 2 patients with LBP disease received the VP regimen (vindesine, 4 mg per dose administered weekly; prednisone, 60 mg/m2 administered daily from Days 1 to 14, with the dose gradually reduced by one-third starting on Day 15 and continuing to decrease by one-third daily through Day 28). Most patients were hospitalized during the initial 7 days of each treatment cycle, after which they were discharged to continue TKI monotherapy at home for the remaining 21 days.
Figure 1.
Study design. The HHT dose was 2 mg/m2 for 7 days and was reduced according to the patient’s bone marrow suppression, heart, and infection conditions. The VP regimen was as follows: vindesine 4 mg/dose administered weekly; prednisone 60 mg/m2 administered daily from Days 114, with the dose gradually reduced by one-third starting on Day 15 and continuing to decrease by one-third daily through Day 28.
Table 1.
Baseline characteristics of the enrolled patients.
| Patients | n = 36 |
|---|---|
| Sex (M/F) | 27/9 |
| Age (years) | |
| Median (range) | 51 (24-77) |
| CML phase | n (%) |
| Accelerated | 13 (36.1) |
| Blast | 23 (63.9) |
| Karyotype | n (%) |
| Not available | 7 (19.4) |
| Philadelphia chromosome only | 18 (50.0) |
| Additional cytogenetic abnormalities (ACAs) a | 11 (30.1) |
| BCR::ABL1 kinase mutation | n (%) |
| No mutation | 21 (58.3) |
| Not available | 4 (11.1) |
| ABL1 kinase mutations | 11 (30.6) |
| F317L/F359V | 1 (2.8) |
| F317L | 1 (2.8) |
| Y253H | 1 (2.8) |
| T315I | 2 (5.6) |
| E255K | 1 (2.8) |
| E255K/V | 1 (2.8) |
| V379I/M244V | 1 (2.8) |
| H396P | 1 (2.8) |
| M244V/T315I | 1 (2.8) |
| Q252H (P-Loop) | 1 (2.8) |
| TKI therapy | n (%) |
| Imatinib | 1 (2.8) |
| Dasatinib | 15 (41.6) |
| Flumatinib | 15 (41.6) |
| Ponatinib | 2 (5.6) |
| Olverembatinib | 3 (8.3) |
aMajor route ACAs: 8+; i17; + Ph. Minor route ACAs: t (3; 12); t (4; 6); t (2; 16); t (1; 21); CML, chronic myeloid leukemia; ACA, additional chromosomal abnormalities.
Figure 2.
Enrollment and outcomes.
Efficacy assessment
Hematologic response assessments were conducted at baseline (pre-study) and on day 1 of each treatment cycle. Morphological and cytogenetic analyses utilized bone marrow samples, while BCR::ABL1 transcript levels were quantified via RT-qPCR in both peripheral blood and bone marrow specimens collected concurrently.
Response criteria followed ELN guidelines, encompassing hematologic (CHR, NEL, MaHR), cytogenetic (PCyR, CCyR), and molecular categories (EMR, MR2.0, MMR, MR4.0, MR4.5, UMD).
Response criteria—categorized as hematologic (CHR, NEL, MaHR), cytogenetic (PCyR, CCyR), and molecular (EMR, MR2.0, MMR, MR4.0, MR4.5)—were defined per ELN recommendations.21,22 Molecular response thresholds on the International Scale (IS) were defined as follows: EMR (≤10% at 3 months), MR2.0 (≤1%), MMR (≤0.1%), MR4.0 (≤0.01%), and MR4.5 (≤0.0032%). UMD was defined as the absence of detectable BCR::ABL1 transcripts in the presence of amplifiable ABL1 transcripts. Molecular monitoring was performed using standardized IS-based assays across participating centers, with central review of molecular response categories to ensure consistency.
Progression-free survival (PFS) was defined as the interval from treatment initiation to disease progression, death, or censoring at the last follow-up. Overall survival (OS) spanned from the first effective dose administration to all-cause mortality or censoring at the final observation. 23
Statistical analysis
The efficacy and safety analyses encompassed participants receiving ≥1 treatment cycle. Baseline non-responders were evaluated for therapeutic responses, while the safety population comprised all individuals completing ≥1 cycle.
Survival endpoints—sustained response duration, PFS, and OS—were estimated via Kaplan-Meier methodology. Two-sided P values derived from log-rank testing defined statistical significance (threshold: P<0.05). Treatment-emergent adverse events (TEAEs) were quantified through incidence analysis.
Cox proportional hazards regression incorporating pretreatment baseline characteristics as covariates identified OS predictors. The covariates included age (≤50 vs. >50 years), sex (male vs. female), CML phase (AP vs. BP), TKI generation (pre-second generation vs. third generation), ABL1 kinase mutation status (presence vs. absence), white blood cell (WBC) count, platelet (PLT) count, and BCR::ABL1 IS level. Results were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs), applying Wald test-derived significance criteria (P<0.05). Variables demonstrating univariate significance (P<0.05) entered multivariate modeling to mitigate overfitting risks.
The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement. 24
Results
Patient characteristics
From June 2021 to July 2024, a total of 41 patients were enrolled in the study. After 5 patients who withdrew prior to completing the first treatment cycle and were lost to follow-up were excluded, 36 patients remained eligible for inclusion in the clinical trial: 23 with BP-CML and 13 with AP-CML. The median age was 51 years, ranging from 24 to 77 years. Eleven patients had additional chromosomal abnormalities, 25 all of which were major-route additional clonal abnormalities. Thirteen patients were found to have BCR::ABL1 kinase mutations. The patient characteristics are summarized in Table 1.
Survival
Among the 36 enrolled patients, all received at least one cycle of therapy, with decreasing numbers completing subsequent cycles: 26 patients received two cycles, 18 received three cycles, 14 received four cycles, 9 received five cycles, and 5 patients received all six planned treatment cycles (Figure 2). Two patients progressed from having AP-CML to having BP-CML, and 16 patients died due to disease progression. Additionally, 1 patient died from gastrointestinal hemorrhage. The median follow-up period was 28.1 months (range: 0.4-36.0) from the start of treatment. The median OS was not reached, and the median PFS was 8.17 months (95% CI: 4.2-12.1 months) (Figure 3). The 3-year OS and PFS rates were 50.3% (95% CI: 32.7-65.6%) and 41.1% (95% CI: 24.0-57.5%), respectively. By the end of follow-up, 7 patients with AP-CML and 12 patients with BP-CML were alive, with no significant differences in OS (not reached vs. 13.13 months, respectively; P=0.57) or PFS (8.77 vs. 6.2 months, respectively; P=0.58) between the two groups (Figure 4(A)/4B).
Figure 3.
Overall Survival and Progression-free Survival. The rates of overall survival (blue line) and progression-free survival (red line) for all patients are shown. The circles indicate censored data.
Figure 4.
Overall Survival and Progression-free Survival, according to disease phase. The rates of overall survival (a) and progression-free survival (b) for all patients according to disease phase (accelerated phase (AP, blue line) and blast phase (BP, red line)) are shown. The circles indicate censored data.
With respect to survival outcomes, patients who achieved MaHR had a significantly longer median OS than did nonresponders (not reached vs. 6.7 months, respectively; P=0.005) (Figure 5(A)). Patients who achieved MCyR had a longer median OS than did those who achieved suboptimal cytogenetic response (SCyR) (not reached vs. 13.13 months, respectively), but the difference was not statistically significant (P=0.17) (Figure 5(B)). Comparisons between patients with a molecular response less than MR2.0 and those who achieved EMR, MMR or UMD provided important insights. These results suggest that patients who achieve an earlier or deeper molecular response during treatment have a significantly longer OS (not reached) than those who achieve a molecular response less than MR2.0 (8 months, P=0.03) (Figure 5(C)).
Figure 5.
Survival analysis of patients stratified into different groups to evaluate the impact of grouping on overall survival. Kaplan-Meier survival curves are shown for each group, and significant differences were assessed using the log-rank test. (a). Impact of achieving MaHR on survival. MaHR: patients who achieved major Hematologic response; NoMaHR: patients who did not achieve major Hematologic response. (b). Impact of achieving cytogenetic response (CyR) on survival. ≤PCyR: patients who achieved only partial cytogenetic response or less; CCyR: patients who achieved complete cytogenetic response. (c). Impact of achieving molecular response (MR) on survival. ≤MR2.0: patients who only achieved molecular response with BCR::ABL1 IS ≤ 1% or less; EMR/MMR/UMD: patients who achieved early molecular response, major molecular response, or undetectable minimal disease.
Response to treatment
Among the 36 patients who completed the first treatment cycle, 61.1% (22/36) achieved MaHR, including 52.8% (19/36) achieving CHR and 8.3% (3/36) achieving NEL. By the end of the first cycle, 26 patients remained in the study: 2 transitioned to HSCT after achieving MaHR, 3 discontinued due to lack of efficacy, and 5 died due to disease progression. The MaHR rate increased to 69.2% (18/26) after the second cycle, with the rates of patients achieving CHR or NEL increasing to 61.5% (16/26) and 7.7% (2/26), respectively. Subsequent cycles demonstrated progressive improvements in the rates of patients achieving MaHR: 66.7% (12/18) after the third cycle, 85.7% (12/14) after the fourth, 66.7% (6/9) after the fifth, and 100% (5/5) by the sixth (Table 2). Overall, 63.9% (23/36) of patients achieved MaHR during the study period, at a median time of 1.33 months (range: 0.17-28.1).
Table 2.
Hematologic response rate after each treatment cycle.
| Hematologic response | ||||
|---|---|---|---|---|
| Assessment | CHR | NEL | NoMaHR | |
| Number of Patients/total number (percent) | ||||
| After cycle 1 | 36 | 19/36 (52.8) | 3/36 (8.3) | 14/36 (38.9) |
| After cycle 2 | 26 | 16/26 (61.5) | 2/26 (7.7) | 8/26 (30.8) |
| After cycle 3 | 18 | 9/18 (50.0) | 3/18 (16.7) | 6/18 (33.3) |
| After cycle 4 | 14 | 9/14 (64.2) | 3/14 (21.4) | 2/14 (14.4) |
| After cycle 5 | 9 | 5/9 (55.6) | 1/9 (11.1) | 3/9 (33.3) |
| After cycle 6 | 5 | 3/5 (60.0) | 2/5 (40.0) | 0/5 (0) |
MCyR was achieved in 11.1% (4/36) of patients after the first cycle, 26.9% (7/26) after the second, 44.4% (8/18) after the third, 42.9% (6/14) after the fourth, 44.4% (4/9) after the fifth, and 40% (2/5) by the sixth (Table 3).
Four patients underwent HSCT and subsequently received maintenance therapy with TKIs, with no relapses observed during the follow-up period (Table 3). Eligibility required attainment of at least CHR prior to HSCT. Among them, two patients completed all six planned cycles of therapy before transplantation, with one achieving pre-HSCT CHR, CCyR, and MMR and the other achieving only a CHR and MR2.0. The remaining two patients received only one cycle of therapy before transplantation, achieving CHR but no cytogenetic or molecular responses (Table 4).
Table 3.
Cytogenetic response rate after each treatment cycle.
| Cytogenetic response | ||||
|---|---|---|---|---|
| Assessment | CCyR | PCyR | SCyR | |
| Number of patients/total number (percent) | ||||
| After cycle 1 | 36 | 4/36 (11.1) | 0/36 (0.0) | 32/36 (89.1) |
| After cycle 2 | 26 | 7/26 (26.9) | 0/26 (0.0) | 19/26 (73.1) |
| After cycle 3 | 18 | 6/18 (33.3) | 2/18 (11.1) | 10/18 (55.6) |
| After cycle 4 | 14 | 5/14 (35.7) | 1/14 (7.1) | 8/14 (57.1) |
| After cycle 5 | 9 | 3/9 (33.3) | 1/9 (11.1) | 5/9 (55.6) |
| After cycle 6 | 5 | 2/5 (40.0) | 0/5 (0.0) | 3/5 (60.0) |
No molecular responses (MRs) were observed by the end of the first treatment cycle. However, after the second cycle, 7.6% (2/26) of patients achieved EMR, 3.8% (1/26) achieved MMR, and 7.6% (2/26) achieved UMD. After the third cycle, 11.1% (2/18) of patients achieved EMR, and 5.6% (1/18) achieved UMD. After the fifth cycle, 7.1% (1/14) of patients achieved MR2.0, and 7.1% (1/14) achieved MMR. By the final cycle, 40% (2/5) of patients reached MR2.0, 20% (1/5) achieved MMR, and 20% (1/5) achieved UMD (Table 4).
Table 4.
Molecular response rate after each treatment cycle.
| Molecular response | ||||||
|---|---|---|---|---|---|---|
| Assessment | EMR | MR2.0 | MMR | UMD | SMR * | |
| Number of patients/total number (percent) | ||||||
| After cycle 1 | 36 | 0/36 (0.0) | 0/36 (0.0) | 0/36 (0.0) | 0/36 (0.0) | 0/36 (0.0) |
| After cycle 2 | 26 | 2/26 (7.6) | 0/26 (0.0) | 1/26 (3.8) | 2/26 (7.6) | 21/26 (80.8) |
| After cycle 3 | 18 | 2/18 (11.1) | 0/18 (0.0) | 0/18 (0.0) | 1/18 (5.6) | 15/18 (83.3) |
| After cycle 4 | 14 | 0/14 (0.0) | 1/14 (7.1) | 1/14 (7.1) | 0/14 (0.0) | 12/14 (85.7) |
| After cycle 5 | 9 | 0/9 (0.0) | 2/9 (22.2) | 1/9 (11.1) | 1/9 (11.1) | 5/9 (55.6) |
| After cycle 6 | 5 | 0/5 (0.0) | 2/5 (40.0) | 1/5 (20.0) | 1/5 (20.0) | 1/5 (20.0) |
The 3-year cumulative incidences of achieving MCyR, MR2.0, MMR and UMD were 48.5% (95% CI: 29.4-71.7%), 16.3% (95% CI: 6.4-37.8%), 21.8% (95% CI: 8.3-50.2%) and 14.2% (95% CI: 4.4-40.4%), respectively (Figure 6).
*SMR: suboptimal molecular response.
Prognostic factors for patient survival
The results of univariate and multivariate (Figure 6) Cox regression analyses are presented in Figure 7. In the univariate analysis, the WBC count was significantly correlated with survival outcomes (HR=1.13, 95% CI: 1.06-1.22, P=0.001). Additionally, BCR::ABL1 IS was identified as another significant prognostic factor (HR=1.70, 95% CI: 1.20-2.42, P=0.003). Other variables, including age (HR=0.90, 95% CI: 0.35-2.35, P=0.84), sex (HR=1.93, 95% CI: 0.55-6.74, P=0.30), CML phase (HR=1.33, 95% CI: 0.49-3.60, P=0.58), TKI generation (HR=0.95, 95% CI: 0.21-4.18, P=0.94), ABL1 kinase mutation status (HR=1.37, 95% CI: 0.50-3.73, P=0.55), and PLT (HR=0.999, 95% CI: 0.998-1.001, P=0.26), were not significantly associated with survival outcomes.
Figure 6.
Cumulative incidence of cytogenetic and molecular responses.
Figure 7.
Results from univariate and multivariate analyses of variables affecting survival outcomes. Univariate (left panel) and multivariate (right panel) analyses of prognostic factors are presented, with hazard ratios (HRs) and 95% confidence intervals (CIs) displayed for each variable.
Variables showing significance in the univariate analysis were further examined in the multivariate analysis. The multivariate analysis confirmed that both the WBC count (HR=1.105, 95% CI: 1.03-1.19, P=0.009) and BCR::ABL1 IS (HR=1.498, 95% CI: 1.07-2.10, P=0.02) remained independent prognostic factors. These findings suggest that an elevated WBC count and higher BCR::ABL1 IS ratio are independently associated with poorer outcomes. In addition, no significant association between TKI generation and treatment outcomes was observed in exploratory subgroup analyses (Supplementary Figure S1).
Treatment-emergent adverse events
20 patients (55.6%) experienced hematologic toxicities of grade 3 or higher. Among them, neutropenia (<0.5×109/L) occurred in 13 patients (36.1%), of whom 8 (22.2%) had febrile neutropenia. Thrombocytopenia (<50×109/L) was observed in 12 patients (33.3%), and 5 patients presented with concurrent neutropenia and thrombocytopenia (Table 5). The median times to resolution for neutropenia and thrombocytopenia were 21 days (range, 5-158) and 17 days (range, 10-160 days), respectively. These conditions were managed via administration of granulocyte colony-stimulating factor or thrombopoietin. 4 patients (11.1%) reported gastrointestinal adverse reactions (nausea/vomit/bloating), and one patient (2.8%) developed pleural effusion that resolved with closed thoracic drainage and did not recur. Another patient experienced severe complication, including severe pneumonia, Escherichia coli septicemia, acute peritonitis, disseminated intravascular coagulation, and heart failure, leading to treatment abandonments and subsequent death. As these events occurred prior to therapy, they were not included in the treatment-emergent adverse event analysis (Table 5). Based on their timing and clinical presentation, these complications were considered more likely related to the underlying disease than to study treatment. Hematologic toxicities and gastrointestinal adverse reactions observed during treatment were considered consistent with the known safety profiles of both azacitidine and TKIs, whereas the pleural effusion was considered more likely related to TKI therapy.
Table 5.
Treatment-emergent adverse events.
| | Patients (%) |
|---|---|
| Hematologic toxicities | 20 (55.6) |
| Thrombocytopenia (<50 × 109 cells/L) or platelet infusion | 12 (33.3) |
| Neutropenia (<0.5×109 cells/L) | 13 (36.1) |
| Febrile neutropenia | 8 (22.2) |
| Nonhematologic toxicities | 5 (13.9) |
| Digestive system adverse reactions (nausea/vomit/bloating) | 4 (11.1) |
| Pleural effusion | 1 (2.8) |
Discussion
We report that the combination regimen of TKIs with azacitidine demonstrated favorable tolerability and efficacy in patients with advanced-phase CML. This regimen also exhibited robust and durable antitumor activity in patients with BP-CML, a disease state characterized by significant biological heterogeneity and associated treatment challenges. 26
With a median follow-up of 28.1 months (range: 0.4-36.0), the median OS was not reached, and the 3-year OS and PFS rates were 50.3% (95% CI: 32.7-65.6%) and 41.1% (95% CI: 24.0-57.5%), respectively. Notably, the regimen induced rapid hematologic responses: 63.9% of patients cumulatively achieved MaHR at a median time of 1.33 months (range: 0.17-28.1), 61.1% achieved MaHR after the first cycle, and all five patients who completed six cycles achieved MaHR. In our study, achieving MaHR was significantly associated with improved survival outcomes. These findings highlight the regimen’s capacity to rapidly stabilize disease and bridge patients to curative interventions such as HSCT. Nevertheless, given that only four patients underwent transplantation, this observation should be interpreted cautiously and validated in larger cohorts. Indeed, transplanted patients exhibited superior long-term outcomes, which aligns with evidence that HSCT remains a cornerstone for the management of advanced-phase CML.8,27 Our study indicates that achieving EMR, MMR or UMD is a favorable prognostic factor associated with improved survival outcomes in patients; these findings underscore the potential clinical benefit of earlier or deeper molecular responses. 28 Further research with larger cohorts and longer follow-up periods is warranted to confirm these observations.
Cox regression analysis identified the baseline WBC count and BCR::ABL1 transcript level as independent prognostic determinants. Each increase in the WBC count of 1 × 10^9 cells/L conferred a 10.5% increase in mortality risk (HR: 1.105, 95% CI: 1.03-1.19, P=0.009), whereas a 100% increase in BCR::ABL1 transcript level was associated with a 49.8% elevated risk of death (HR: 1.498, 95% CI: 1.07-2.10, P=0.02). These observations corroborate prior studies linking a high WBC count (>150 × 10^9 cells/L) and elevated BCR::ABL1 IS (>10%) at 3 months with reduced rates of patients achieving deep molecular response (DMR).29,30 However, ABL1 kinase mutations did not independently predict survival, likely due to the limited sample size and individualized TKI selection based on mutation profiles, which may mitigate their adverse effects. Similarly, TKI generation (first-vs. second-vs. third-generation) was not associated with prognosis, exploratory analyses according to TKI generation showed no significant differences in survival or treatment responses between groups (Supplementary Figure S1). However, the limited number of patients treated with third-generation TKIs precludes definitive conclusions regarding the relative efficacy of individual TKIs. Due to the small cohort, the prognostic model should be interpreted cautiously, and validation in larger datasets is required to confirm these predictors.
Both myeloid and lymphoid blast crisis cases were included in this study. Although azacitidine is primarily used in myeloid malignancies, recent evidence demonstrates that blast crisis CML exhibits extensive promoter hypermethylation and Polycomb-mediated gene silencing, suggesting a shared epigenetic mechanism across lineages. 31 Furthermore, ABL1 promoter methylation has been reported in Philadelphia chromosome–positive acute lymphoblastic leukemia, 32 supporting the rationale for applying hypomethylating therapy even in lymphoid-type blast crisis.
Compared with historical cohorts receiving TKI monotherapy or TKI combined with intensive chemotherapy,33,34 our regimen achieved superior early response rates (61.1% of patients achieved MaHR after the first cycle) with reduced toxicity. AEs were predominantly hematologic (grade ≥3 in 55.6% of patients), manageable through supportive care, and resolved within short intervals. Only 4 patients (11.1%) experienced nonhematologic AEs, underscoring the regimen’s favorable safety profile and potential to improve quality of life during treatment. 35 A recent phase II trial 36 reported that the triplet regimen of decitabine, venetoclax, and ponatinib achieved a marrow remission (CR+CRi+MLFS) rate of 80% and a median OS of 11.1 months in advanced-phase CML/Ph+ AML. Compared with our TKI–azacitidine regimen (MaHR 63.9%, 3-year OS 50.3%), the triplet produced deeper responses but with substantially higher myelosuppression. These findings indicate that the HMA–TKI doublet remains an effective and tolerable option for patients unfit for intensive therapy. Nevertheless, achieving durable deep molecular remission remains challenging across treatment strategies. In the triplet study, major molecular response and complete molecular response were achieved in only 5% and 15% of patients, respectively.
The dual targeting of BCR::ABL1 oncogenic signaling (via TKIs) and epigenetic dysregulation (via azacitidine) likely underlies the observed efficacy, particularly in overcoming TKI resistance in patients with BP-CML. 25 This synergy enables rapid disease control, facilitating timely HSCT in eligible patients—two of four transplanted patients transitioned after just one treatment cycle. Nevertheless, the rates of patients achieving deeper molecular responses, such as MMR and UMD, remained suboptimal, with 3-year cumulative incidences of 21.8% (95% CI: 8.3-50.2%) and 14.2% (95% CI: 4.4-40.4%), respectively. These findings suggest that hypermethylation is not the sole driver of CML progression and that sustained BCR::ABL1 activity promotes genomic instability and diverse molecular aberrations. Future studies should explore adjunctive therapies targeting alternative pathways to increase the depth and durability of responses.
Limitations
Several limitations should be acknowledged. First, this was a single-arm, non-randomized study with a relatively small sample size, which may limit the generalizability of the findings and precludes direct comparisons with other treatment regimens. Second, five enrolled patients discontinued participation before completing the first treatment cycle and had no post-baseline efficacy assessments available, precluding a formal intention-to-treat analysis. Their exclusion may have introduced selection bias and potentially resulted in an overestimation of response rates and survival outcomes. Third, multiple TKIs were used. Although no significant differences were observed between TKI generations (Supplementary Figure S1), the small number of patients receiving third-generation TKIs warrants cautious interpretation of these comparisons. Fourth, only four patients proceeded to allogeneic HSCT, therefore, the potential role of this regimen as a bridge to transplantation should be interpreted cautiously. Fifth, detailed data on dose reductions and treatment delays were not systematically collected, and attribution of adverse events was based on clinical judgment and temporal association rather than a standardized algorithm. Nevertheless, the observed adverse events were consistent with the established safety profiles of azacitidine and TKIs, supporting the overall safety findings of the present study. Future studies with more comprehensive safety monitoring may provide additional insights into treatment tolerability.
Conclusion
In summary, the combination of TKIs and azacitidine was associated with rapid hematologic responses and encouraging survival outcomes in advanced-phase CML. Future studies should focus on improving the depth of molecular remission and defining the optimal integration of this approach within evolving treatment paradigms.
Supplemental material
Supplemental material for Dual targeting of BCR::ABL1 and DNA methylation in advanced CML: A 3-year survival analysis of TKI-Azacitidine combination therapy by Zhuming Yang, Danlei Han, Renying Ge, Zhenhao Wang, Hanlin Du, Yigang Guo, Zhe Zhao, Li Liu, Jun Qin, Bangwei Yu, Jie Hu, Xiya Gui, Meifang Su, Shiming Chen, Daozi Jiang, Jing Zheng, Hongxiang Wang, Li Meng, Weiming Li and Zhenya Hong in Therapeutic Advances in Hematology.
Acknowledgements
We gratefully acknowledge the financial support from the National Natural Science Foundation of China (Grant 81873430). We extend our heartfelt thanks to all patients and their families for their participation. We are also indebted to the clinical staff at the participating centers for their support in patient care and data collection.
Appendix.
Abbreviations
- AE
Adverse event
- CCyR
Complete cytogenetic response
- CHR
Complete hematologic response
- CI
Confidence interval
- CML
Chronic myeloid leukemia
- CML-AP
Accelerated-phase chronic myeloid leukemia
- CML-BP
Blast-phase chronic myeloid leukemia
- DMR
Deep molecular response
- ELN
European LeukemiaNet
- EMR
Early molecular response
- HR
Hazard ratio
- LBP
Lymphoid blast phase
- MaHR
Major hematologic response
- MBP
Myeloid blast phase
- MCyR
Major cytogenetic response
- MMR
Major molecular response
- MR2.0
2-log reduction in BCR::ABL1 transcripts on the International Scale (IS): ≤1%
- MR4.0
4-log reduction in BCR::ABL1 transcripts on the International Scale (IS):≤ 0.01%
- MR4.5
4.5-log reduction in BCR::ABL1 transcripts on the International Scale (IS): ≤0.0032%
- NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
- NEL
No evidence of leukemia
- NGS
Next-generation sequencing
- OS
Overall survival
- PCyR
Partial cytogenetic response
- PFS
Progression-free survival
- TKI
Tyrosine kinase inhibitor
- TEAEs
Treatment-emergent adverse events
- UMD
Undetectable minimal disease.
Author contributions: Designed and supervised the study: ZY.H., WM.L. and L.M. Analyzed the data and wrote the manuscript: ZM.Y., DL.H. and RY.G. Enrolled the patient: ZH.W. and HL.D. All authors performed the research and collected the data. All authors had access to primary clinical data and had final responsibility for the decision to submit the manuscript for publication. These authors contributed equally: Zhuming Yang, Danlei Han, Renying Ge. All authors read and approved the final manuscript.
Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work is supported by funding from the National Natural Science Foundation of China (Grant 81873430 [Zhenya Hong]).
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Supplemental material: Supplemental material for this article is available online.
ORCID iD
Zhuming Yang https://orcid.org/0009-0007-6931-6344
Ethical considerations
Studies were conducted in compliance with the Declaration of Helsinki, with protocols approved by institutional review boards and registered at the Medical Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology (2020-S348).
Consent to participate
Written informed consent was obtained from all patients prior to the initiation of any study-specific procedures.
Consent for publication
Informed consent for publication was obtained from all patients included in the study.
Data Availability Statement
The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.*
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental material for Dual targeting of BCR::ABL1 and DNA methylation in advanced CML: A 3-year survival analysis of TKI-Azacitidine combination therapy by Zhuming Yang, Danlei Han, Renying Ge, Zhenhao Wang, Hanlin Du, Yigang Guo, Zhe Zhao, Li Liu, Jun Qin, Bangwei Yu, Jie Hu, Xiya Gui, Meifang Su, Shiming Chen, Daozi Jiang, Jing Zheng, Hongxiang Wang, Li Meng, Weiming Li and Zhenya Hong in Therapeutic Advances in Hematology.
Data Availability Statement
The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.*