Real-life comparison of Nilotinib versus Dasatinib as second-line therapy in chronic phase chronic myeloid leukemia patients

* Corresponding author: Wiam HABERROU Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution License 4.0. Real-life comparison of Nilotinib versus Dasatinib as second-line therapy in chronic phase chronic myeloid leukemia patients Wiam HABERROU 1, 2, *, Hamza BENBACHIR 2, Manel SEDDIKI 1, 2, Badra ENTA SULTAN 3 and Houari TOUMI 1, 2 1 Department of Pharmacovigilance, University Hospital of Oran. 2 Department of Pharmacy, Faculty of Medicine, Oran. 3 Department of Hematology, University Hospital of Oran. GSC Biological and Pharmaceutical Sciences, 2025, 33(02), 093-105 Publication history: Received on 27 September 2025; revised on 01 November 2025; accepted on 04 November 2025 Article DOI: https://doi.org/10.30574/gscbps.2025.33.2.0432 Abstract Introduction: Chronic myeloid leukemia (CML) is a rare hematologic malignancy whose management has been transformed by tyrosine kinase inhibitors (TKIs). After failure or intolerance to Imatinib, Dasatinib and Nilotinib are commonly used as second-line therapies. This study aimed to compare their tolerance and efficacy in real-world practice. Patients and Methods: A retro-prospective study was conducted at the University Hospital of Oran (2013–2025), including 45 patients with chronic phase CML who switched from imatinib to a second-generation TKI (24 dasatinib, 21 nilotinib). Responses were assessed according to ELN 2020 and GAT-LMC criteria, toxicities were graded using CTCAE, and progression-free survival (PFS) and event-free survival (EFS) were analyzed using Kaplan-Meier. Results and Discussion: The mean age was 45 years, and the main reason for switching was Imatinib resistance (84%). Regarding tolerance, Nilotinib was associated with metabolic and hepatobiliary toxicities (hyperbilirubinemia 19%),cutaneous toxicity (hyperkeratosis 19%), and cardiovascular toxicity (9.5%) , while Dasatinib was more frequently linked to anemia (25%) and pleural effusion (16.7%). Concerning molecular response, Nilotinib showed faster responses at 6 months (69% vs. 50% by ELN; 84.6% vs. 58.3% by GAT-LMC), but this trend reversed after 18 months, with better longterm response rates and persistence under Dasatinib. Survival analysis showed similar PFS between the two agents (101 months vs. 89.7 months; p = 0.880), while EFS favored Dasatinib (80 vs. 58.6 months). These findings suggest distinct response kinetics and safety profiles: Nilotinib induces earlier molecular responses but with more treatment interruptions, whereas Dasatinib ensures better long-term persistence. Conclusion: In second-line therapy, Dasatinib and Nilotinib show comparable efficacy but distinct tolerance and response dynamics. Therapeutic choice should be individualized according to the patient’s clinical and comorbidity profile: Nilotinib may be preferred for rapid molecular control, while Dasatinib appears better suited for long-term consolidation. These results highlight the importance of personalized follow-up in the management of CML in Algeria. Keywords: Chronic myeloid leukemia; Tyrosine kinase inhibitors; Dasatinib; Nilotinib; Second-line therapy; Efficacy; Tolerance 1. Introduction Chronic myeloid leukemia (CML) is a rare malignant hematologic disorder classified among the myeloproliferative neoplasms, with a global incidence estimated at 1 to 2 cases per 100,000 individuals. In Algeria, it ranks as the fifth most common cancer, with a steadily rising incidence from 0.4 cases per 100,000 in 2004 to 0.53 in 2014 [1,2]. GSC Biological and Pharmaceutical Sciences, 2025, 33(02), 093-105 94 Biologically, CML is characterized by the presence of the Philadelphia chromosome (Ph), resulting from a reciprocal translocation between chromosomes 9 and 22 [t(9;22)]. This genetic abnormality leads to the fusion of the ABL oncogene from chromosome 9 with the BCR (Breakpoint Cluster Region) gene from chromosome 22, forming the BCR-ABL fusion gene. The resulting chimeric gene encodes an oncogenic protein with constitutively high tyrosine kinase (TK) activity, responsible for abnormal activation of intracellular signaling pathways involved in uncontrolled proliferation and prolonged survival of leukemic myeloid cells [3]. Historically, CML was associated with a poor prognosis, inevitably progressing to acute leukemia. This unfavorable trajectory was significantly altered by the emergence of targeted therapies, particularly tyrosine kinase inhibitors (TKIs). Imatinib, the first TKI launched in 2001, revolutionized the management of the disease by significantly improving survival compared to previous therapies such as interferon-alpha and cytarabine [4]. According to a recent update from the IRIS study, the 10-year overall survival with first-line Imatinib reaches nearly 80%. However, approximately 15 to 20% of patients develop resistance or intolerance to Imatinib, thereby requiring the use of a second-generation tyrosine kinase inhibitor (2G-TKI) [5]. The updated 2020 guidelines of the European LeukemiaNet (ELN) [6,7] define resistance based on the depth of molecular response in addition to complete hematologic response (CHR). Intolerance is defined by the occurrence of persistent or recurrent grade 3 or 4 adverse events despite appropriate co-medication or hygiene-dietary measures. Nilotinib and Dasatinib, two second-generation TKIs, play a crucial role in the treatment of chronic-phase CML (CP-CML). These agents have demonstrated outstanding efficacy in both firstand second-line settings, inducing deeper and faster molecular responses and reducing progression to accelerated or blast phase compared to Imatinib [8]. Their superiority has been established in several randomized clinical trials involving newly diagnosed CP-CML patients, notably the ENESTnd (for Nilotinib) and DASISION (for Dasatinib) studies, where each TKI was compared to Imatinib. After 10 years of follow-up, these trials reported high cumulative rates of major molecular response (MMR)—88.2% for Dasatinib and 79.7% for Nilotinib—with similar overall survival rates: 89% for Dasatinib and 87.6% for Nilotinib [9,10]. However, real-world data directly comparing second-generation TKIs remain limited. Two recent studies—one retrospective and multicenter, the other monocentric—have confirmed comparable efficacy between Dasatinib and Nilotinib when used as second-line treatments [11,12]. The comparison of the efficacy and tolerability of Dasatinib and Nilotinib in the treatment of chronic-phase CML (CP-CML) is of major importance, particularly to optimize therapeutic decisions based on patients’ clinical profiles [13]. In Algeria, these two second-generation TKIs are generally reserved for second-line use due to their high cost. The selection between Dasatinib and Nilotinib largely depends on individual clinical characteristics and the specific safety profile of each drug. The objective of our study was to evaluate and compare, under real-world conditions, the efficacy and tolerability of Dasatinib and Nilotinib when used as second-line treatment in a monocentric cohort of CP-CML patients exhibiting resistance and/or intolerance to Imatinib. 2. Patients and Methods This study is a retro-prospective, descriptive, and analytically oriented analysis conducted in the Hematology Department in collaboration with the Pharmacovigilance Unit of the University Hospital of Oran (EHU Oran), covering the period from January 1, 2013, to June 30, 2025. Included were patients over 18 years of age diagnosed with chronic-phase CML (CP-CML), initially treated with Imatinib as first-line therapy, and subsequently switched to a second-generation TKI (2G-TKI) due to resistance or intolerance. Eligible patients were required to have a regular and well-documented medical follow-up within the department, including molecular biology data available at least at two evaluation time points (6, 12, or 18 months). Noninclusion criteria included patients in accelerated or blast phase at the time of treatment switch or those with incomplete medical records. Data were collected from patients’ medical records (follow-up sheets, biological tests, molecular results) and completed using a dedicated follow-up form. The variables analyzed included demographic characteristics, comorbidities, Sokal and EUTOS prognostic scores, BCR-ABL transcript type, the second-line TKI administered with initial dosage, reasons for switching, duration of exposure to treatment, and any treatment interruptions. Treatment responses were evaluated based on the updated criteria from the European LeukemiaNet (ELN 2020) [7] and The Algerian Working Group on LMC (GATLMC) [14], taking into account BCR-ABL levels at 3, 6, 12, 18, and 24 months, depending on the availability of molecular monitoring. Adverse events (AEs) occurring during second-line treatment were recorded and classified according to their severity using the Common Terminology Criteria for Adverse Events (CTCAE) [15]. GSC Biological and Pharmaceutical Sciences, 2025, 33(02), 093-105 95 Data analysis was conducted using an intention-to-treat approach to best reflect real-world treatment conditions. All patients initially assigned to either therapeutic group (Dasatinib or Nilotinib) were retained for longitudinal analysis of efficacy and tolerability, regardless of subsequent treatment modifications. Patients who discontinued treatment before an evaluation point due to resistance were considered non-responders in response rate calculations. Those who stopped due to intolerance were classified as intolerant but were not counted as treatment failures. However, both profiles (resistance and intolerance) were included in the global longitudinal response analysis to avoid bias in interpreting therapeutic evolution. Conversely, patients still under treatment but lacking BCR-ABL quantification at a specific time point (due to logistical issues) were excluded from the response rate calculation at that particular time to limit bias from missing data. Therapeutic efficacy was assessed through molecular responses at various time points, as well as progression-free survival (PFS) and event-free survival (EFS), both estimated using the Kaplan–Meier method, with survival curves compared via the Log-Rank test.Tolerability was evaluated by documenting adverse events, with a comparative analysis between the two treatment groups using Pearson’s Chi-squared test. A p-value < 0.05 was considered statistically significant. Table 1 Baseline demographic, clinical, and treatment characteristics Variable Effective Total (n=45) % Total Effective Dasatinib (n=24) % Dasatinib Effective Nilotinib (n=21) % Nilotinib Gender Male 26 57.8 14 58.3 12 57.1 Female 19 42.2 10 41.7 9 42.9 Age groups 18–34 years 13 28.9 6 25.0 7 33.3 35–49 years 14 31.1 8 33.3 6 28.6 50–65 years 14 31.1 6 25.0 8 38.1 >65 years 4 8.9 4 16.7 0 0.0 Transcript type b2a2 18 40.0 11 45.8 7 33.3 b3a2 15 33.3 7 29.2 8 38.1 Mixed 4 8.9 2 8.3 2 9.5 Sokal Score Low 7 17.1 3 14.3 4 20.0 Intermediate 20 48.8 12 57.1 8 40.0 High 14 34.1 6 28.6 8 40.0 Reason for switching from Imatinib to 2G TKI Resistance 38 84.4 20 83.3 18 85.7 Intolerance 5 11.1 3 12.5 2 9.5 Mixed 2 4.4 1 4.2 1 4.8 Treatment discontinuation Yes 22 48.9 11 45.8 11 52.4 No 23 51.1 13 54.2 10 47.6 Reason for stopping 2nd-line treatment Résistance 12 26.7 7 29.2 5 23.8 Intolérance 8 17.8 3 12.5 5 23.8 Mixte 2 4.4 1 4.2 1 4.8 Associated comorbidities Diabetes 6 13.3 Hypertension 4 8.9 GI disorders 4 8.9 Others 3 6.7 GSC Biological and Pharmaceutical Sciences, 2025, 33(02), 093-105 96 Hypothyroidism 2 4.4 Epilepsy 1 2.2 Hypercholesterolemia 1 2.2 Cross-tabulations were also conducted to explore the potential influence of specific clinical variables on treatment response and overall disease evolution. All statistical analyses were performed using SPSS software (version 21) and Microsoft Excel. 3. Results 3.1. Description of the Study Cohort: The study included 45 patients diagnosed with chronic-phase chronic myeloid leukemia (CML-CP) who were treated with a second-generation tyrosine kinase inhibitor (2G TKI): 24 patients (53.3%) received Dasatinib and 21 patients (46.7%) received Nilotinib. The mean age of the cohort was 45.6 years (median: 45), with a slight male predominance (57.8%), distributed evenly across both treatment groups. More than 90% of patients were under 65 years of age. The median duration of exposure to Imatinib before switching was 18 months (mean: 22 months). The main reason for switching to second-line therapy was resistance to Imatinib (84.4%), with a balanced distribution between the two 2G TKIs. Data on BCR-ABL transcript types showed a predominance of b2a2 (40.0%), followed by b3a2 (33.3%) and the mixed b2a2 + b3a2 profile (8.9%). Regarding prognostic scores, 48.8% of patients were classified as intermediate-risk according to the Sokal score, and 70.7% as low-risk according to the EUTOS score. The Nilotinib group included more patients with high Sokal risk (40% vs. 28.6%). The average duration of treatment with 2G TKIs was 49 months (median: 24 months), with a wide range from 1 to 150 months, reflecting significant heterogeneity in treatment maintenance. Nearly half of the patients (48.9%) discontinued second-line therapy, with a slightly higher rate in the Nilotinib group (52.4%) compared to the Dasatinib group (45.8%). The main reasons for discontinuation were resistance (26.7%) and intolerance (17.8%), with intolerance-related discontinuations more frequent under Nilotinib (23.8% vs. 12.5% under Dasatinib). The most common comorbidities included diabetes (13.3%), arterial hypertension (8.9%), and gastrointestinal disorders (8.9%) (Table 1). 3.2. Evaluation of Toxicities and Adverse Events: The comparative analysis of toxicities revealed several differences between the two inhibitors. A significant elevation in bilirubin levels was observed under Nilotinib (19% vs. 0%; p = 0.025), suggesting moderate cholestatic hepatotoxicity. Other biochemical abnormalities were more frequently reported with Nilotinib, including elevated transaminases (9.5%), GGT (9.5% vs. 4.2%), ALP (4.8% vs. 4.2%), and hyperglycemia (9.5% vs. 4.2%), though these differences were not statistically significant. Grade 2–3 anemia was significantly more frequent with Dasatinib (25.0% vs. 0%; p = 0.048), while severe thrombocytopenia was more common with Nilotinib (23.8% vs. 12.5%), without reaching statistical significance (p = 0.270). Neutropenia was moderate and comparable between both groups. Hyperkeratosis was reported more frequently with Nilotinib (19.0% vs. 0%; p = 0.025), whereas pruritus (9.5% vs. 8.3%) and skin rashes (4.8% vs. 4.2%) were rare and similar in both groups. Regarding cardiopulmonary complications, Dasatinib was associated with a significantly higher rate of pleural effusions (16.7% vs. 0%; p = 0.050), often accompanied by dyspnea (16.7% vs. 4.8%), as well as edema and pulmonary arterial hypertension (8.3% each). In contrast, cardiovascular events occurred only under Nilotinib (9.5%). Diarrhea was more common with Dasatinib (50% vs. 19%), while constipation (14.3% vs. 4.2%), anorexia (33.3% vs. 20.8%), and nausea (33.3% vs. 25.0%) were more frequently reported under Nilotinib, though without significant differences. Finally, arthralgia/myalgia was frequent in both groups (47.6% with Nilotinib vs. 41.7% with Dasatinib), and pronounced asthenia was more commonly reported under Nilotinib (76.2% vs. 50%; p = 0.071) (Table 2). GSC Biological and Pharmaceutical Sciences, 2025, 33(02), 093-105 97 Table 2 Adverse Events and Toxicities by Treatment Group in the Study Population Adverse Event Total n (%) Dasatinib n (%) Nilotinib n (%) p (Pearson Chi²) ↑ Transaminases 2 (4.4%) 0 (0.0%) 2 (9.5%) 0.302 ↑ GGT 3 (6.7%) 1 (4.2%) 2 (9.5%) 0.472 ↑ ALP 2 (4.4%) 1 (4.2%) 1 (4.8%) 0.362 ↑ Bilirubin 4 (8.9%) 0 (0.0%) 4 (19.0%) 0.025* Hyperlipasemia 2 (4.4%) 1 (4.2%) 1 (4.8%) 0.923 Hyperglycemia 3 (6.7%) 1 (4.2%) 2 (9.5%) 0.472 Thrombocytopenia 8 (17.8%) 3 (12.5%) 5 (23.8%) 0.270 Anemia 6 (13.3%) 6 (25.0%) 0 (0.0%) 0.048* Neutropenia 6 (13.3%) 3 (12.5%) 3 (14.3%) 0.539 Pruritus 4 (8.9%) 2 (8.3%) 2 (9.5%) 0.889 Skin Rash 2 (4.4%) 1 (4.2%) 1 (4.8%) 0.365 Hyperkeratosis 4 (8.9%) 0 (0.0%) 4 (19.0%) 0.025* Edema 2 (4.4%) 2 (8.3%) 0 (0.0%) 0.176 Pleural Effusion 4 (8.9%) 4 (16.7%) 0 (0.0%) 0.050* Pulmonary Arterial Hypertension (PAH) 2 (4.4%) 2 (8.3%) 0 (0.0%) 0.176 Dyspnea 5 (11.1%) 4 (16.7%) 1 (4.8%) 0.205 Cough 3 (6.7%) 2 (8.3%) 1 (4.8%) 0.632 Cardiovascular Events 2 (4.4%) 0 (0.0%) 2 (9.5%) 0.122 Diarrhea 16 (35.6%) 12 (50.0%) 4 (19.0%) 0.228 Constipation 4 (8.9%) 1 (4.2%) 3 (14.3%) 0.234 Nausea 13 (28.9%) 6 (25.0%) 7 (33.3%) 0.538 Anorexia 12 (26.7%) 5 (20.8%) 7 (33.3%) 0.388 Arthralgia/Myalgia 20 (44.4%) 10 (41.7%) 10 (47.6%) 0.572 Asthenia 28 (62.2%) 12 (50.0%) 16 (76.2%) 0.071 Headache 7 (15.6%) 3 (12.5%) 4 (19.0%) 0.545 Paresthesia 5 (11.1%) 3 (12.5%) 2 (9.5%) 0.713 Weight Gain 4 (8.9%) 3 (12.5%) 1 (4.8%) 0.363 Epistaxis 2 (4.4%) 2 (8.3%) 0 (0.0%) 0.176 3.3. Evaluation of Treatment Response Over Time According to ELN and GAT-LMC Criteria At 6 months, based on the 2020 ELN criteria, 60% of patients achieved an optimal response (BCR-ABL1 ≤ 1%), with an apparent advantage for Nilotinib (69.2%) over Dasatinib (50%). The rate of molecular failure was lower in the Nilotinib group (7.7% vs. 41.7%; p = 0.206). The GAT-LMC criteria, which are more permissive (target: BCR-ABL1 ≤ 10%), confirmed this trend, with 84.6% of patients achieving an optimal response under Nilotinib compared to 58.3% under Dasatinib (p = 0.104) (Figure 1). At 12 months, major molecular response (MMR, BCR-ABL1 ≤ 0.1%) was achieved in 52.8% of patients, with a slight advantage for Nilotinib (55.6% vs. 50%). The failure rate remained higher in the Dasatinib group (38.9% vs. 16.7%; p = GSC Biological and Pharmaceutical Sciences, 2025, 33(02), 093-105 98 0.327). Results according to the GAT-LMC criteria at 12 months (target: BCR-ABL1 ≤ 1%) showed a similar trend, with optimal response rates of 77.8% under Nilotinib and 55.6% under Dasatinib (p = 0.322) (Figure 2). At 18 months, although the MMR was generally maintained (52.3%), a reversal of trend was observed, with higher response rates under Dasatinib (58.3% vs. 45.0%) and better tolerability (intolerance: 8.3% vs. 15.0%). By 24 months, Dasatinib continued to show a slight advantage in terms of response (52.4% vs. 35.3%) and tolerability (9.5% vs. 23.5%), although differences were not statistically significant (p = 0.406) (Figure 3). Figure 1 Molecular Response at 6 Months of Treatment Figure 2 Molecular Response at 12 Months of Treatment GSC Biological and Pharmaceutical Sciences, 2025, 33(02), 093-105 99 Figure 3 Molecular Response at 18 and 24 Months of Treatment 3.4. Analysis of Progression-Free and Event-Free Survival The analysis of progression-free survival (PFS) by treatment group showed a mean duration of 101 months with Dasatinib (90% CI: 77.8–124) and 89.7 months with Nilotinib (90% CI: 69.3–110.1), with median values not reached in either group. At 24 months, PFS rates were estimated at 70.8% for Dasatinib and 73.1% for Nilotinib, with no significant difference (p = 0.880). Based on the reason for switching to a second-generation TKI, 24-month PFS was 70% in patients who switched due to resistance and 75% for those who switched due to intolerance, again with no significant difference (p = 0.632). In terms of gender, mean PFS was 93 months in females and 98 months in males (p = 0.675), with estimated 24-month PFS rates of 77.6% and 68.1%, respectively. Analysis by BCR-ABL transcript type revealed a highly significant difference (p < 0.001). Patients with the b2a2 transcript had the best PFS (100 months), followed by those with b3a2 (89.8 months), while those with the mixed b2a2 + b3a2 transcript had markedly poor PFS (10.5 months, median of 7 months). At 24 months, PFS rates were estimated at 81.4% for b2a2, 73.3% for b3a2, and 0% for the mixed transcript group (Figure 4). As for event-free survival (EFS), which includes both therapeutic failures and intolerances, the mean duration was 80 months with Dasatinib versus 58.6 months with Nilotinib (p = 0.619). The median was reached at 24 months with Nilotinib but not reached with Dasatinib. At 24 months, EFS rates were estimated at 54.2% for Dasatinib and 47.7% for Nilotinib. Finally, gender-based analysis showed a mean EFS of 78.9 months in females compared to 63.1 months in males, with 24month rates of 60.6% and 42.3%, respectively (p = 0.142) (Figure 5). 4. Discussion The studied cohort was characterized by a relatively young average age (45 years), comparable to that reported by Scalzulli et al. [11] (49 years) and Toptas et al. [12] (50 years)—a factor often associated with better adherence and tolerance to TKIs. Most patients presented with a low EUTOS score, reflecting an overall favorable prognostic profile. However, a notable proportion exhibited high Sokal scores (40%), particularly in the Nilotinib group. This contrasts with the 9% reported in the study by Scalzulli et al. [11], suggesting a generally higher-risk population in our series. The median duration of exposure to Imatinib was relatively short (18 months), reflecting early treatment discontinuation due to therapeutic resistance—identified as the main reason for switching to second-generation TKIs in our cohort (84.4%), consistent with the rates reported by Scalzulli et al. [11] (83.2%) and Toptas et al. [12] (85%). This observation supports the idea that, in real-world clinical practice, most treatment switches are driven by therapeutic failure rather than intolerance. The significant heterogeneity observed in the duration of second-generation TKI therapy (median 24 months, range 1 to 150 months) highlights the interindividual variability in treatment tolerance and efficacy. This finding aligns with data from Scalzulli et al. [11] (median 33 months, range 2–100) and Toptas et al. [12] (median of 5 years in both arms), confirming GSC Biological and Pharmaceutical Sciences, 2025, 33(02), 093-105 100 that some patients achieve sustained disease control, while others discontinue treatment early due to failure or limiting side effects. a. Progression-free survival in the cohort b. According to treatment received c. According to sex d. According to BCR-ABL transcript type Figure 4 Progression-Free Survival GSC Biological and Pharmaceutical Sciences, 2025, 33(02), 093-105 101 a. Event-free survival in the cohort b. According to sex c. According to treatment group Figure 5 Event-Free Survival in the Cohort The distribution of BCR-ABL transcripts in our cohort was typical, with a majority of b3a2 and b2a2 variants. However, mixed transcripts were observed in 8.9% of cases—more frequently than in Scalzulli et al. [11] (1.5%)—warranting particular attention due to their known association with poorer molecular prognosis and slower treatment response. Regarding tolerance and therapeutic management of 2G TKIs, nearly half of the patients in our cohort (48.9%) discontinued treatment, reflecting a high rate of treatment withdrawals, more frequently observed in the Nilotinib group. The main reasons for discontinuation were resistance (26.7%) and intolerance (17.8%). Drug-specific analysis showed a higher rate of intolerance-related discontinuation with Nilotinib, suggesting a less favorable tolerance profile likely related to its metabolic and cardiovascular adverse effects. In comparison, the study by Toptas et al. [12] reported similar discontinuation rates for Dasatinib (52.9% vs. 45.8%), while a more marked difference was observed for Nilotinib (30.8% vs. 52.4%). The study by Scalzulli et al. [11] reported an overall discontinuation rate due to intolerance of 13.7%, which was lower than in our cohort. In our series, the notable prevalence of comorbidities (13.3% diabetes, 11.1% hypertension) underscores the need for rigorous multidisciplinary follow-up, particularly in patients treated with Nilotinib.