Adverse reactions of dasatinib in pediatric acute lymphoblastic leukemia: a retrospective comparative cohort study

Introduction

Acute lymphoblastic leukemia (ALL) is a malignant hematologic disorder characterized by the clonal proliferation of immature lymphocytes and infiltration of various tissues. Philadelphia chromosome-positive (Ph⁺) ALL accounts for 2–5% of pediatric cases, while Ph-like ALL is a high-risk subtype with a similar gene expression profile but lacking the BCR::ABL1 fusion gene. Prior to the era of tyrosine kinase inhibitors (TKIs), conventional chemotherapy yielded cure rates below 40%. Dasatinib, a second-generation TKI, has established a crucial role in the treatment of pediatric Ph⁺ ALL and specific subsets of Ph-like ALL (e.g., those involving ABL-class fusions). By potently inhibiting BCR::ABL1 and other key kinases, dasatinib combined with chemotherapy has significantly improved long-term survival and deep molecular response rates in children with Ph⁺ ALL, and has also demonstrated promising efficacy in improving outcomes for eligible patients with Ph-like ALL (1).

For example, imatinib, the first-generation TKI, inhibits the ATP-binding site of BCR-ABL1, preventing the fusion protein from adopting its active conformation (2). However, imatinib has poor blood-brain barrier penetration and is prone to resistance. Second-generation TKIs, designed to overcome imatinib resistance, exhibit stronger kinase inhibition (325-fold more potent) and better central nervous system (CNS) penetration. According to the Chinese Children Cancer Group (CCCG)-ALL-2020 protocol by the Chinese Children’s Cancer Group, dasatinib demonstrates superior efficacy over imatinib (3). Although dasatinib shows better therapeutic outcomes, its safety profile in pediatric patients, as characterized primarily in clinical trials, requires careful consideration. These trials report that dasatinib is generally well-tolerated in children, with common adverse events (AEs) including myelosuppression and transient transaminase elevation (3). However, rare but serious non-hematologic toxicities documented in adults—such as pulmonary arterial hypertension (PAH) (4), pleural effusion (PE) (5), and chylothorax (6)—have also been observed in the pediatric population. The existing evidence on the safety of dasatinib in children has several limitations. Many studies are constrained by relatively small sample sizes, limited long-term follow-up, and homogeneous trial populations under strict monitoring protocols (3). However, in more heterogeneous real-world pediatric populations, particularly when compared with matched non-dasatinib controls, the attributable risk of its specific toxicities remains inadequately defined. Furthermore, whether different genetic backgrounds influence toxicity susceptibility and how to implement effective monitoring and preventive strategies in routine clinical practice remain unmet needs (7).

Therefore, this study aims to systematically compare the AE profiles between pediatric ALL patients treated with and without dasatinib through a retrospective cohort study, in order to more accurately assess its safety profile. Although retrospective in design, the implementation of strict patient inclusion criteria, detailed baseline data collection, and standardized AE assessment tools will enable us to provide important real-world evidence addressing these clinical questions. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-403/rc).

Methods

Ethics

This retrospective single-center clinical study was conducted at Shanghai Children’s Medical Center, Shanghai, China. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University (No. SCMCIRB-K2024123-1). Individual consent for this retrospective analysis was waived.

Participants

This single-center, retrospective cohort study analyzed children diagnosed with ALL at Shanghai Children’s Medical Center between May and September 2024. As an exploratory, hypothesis-generating analysis, no formal sample size calculation was performed. We consecutively enrolled all eligible patients to maximize analytical power. Participants were categorized into a dasatinib group and a control group defined as those not receiving dasatinib. The control group was selected from the same patient population during the identical study period who met the same broad inclusion criteria (diagnosis of ALL, receiving chemotherapy) but did not receive any TKI, including dasatinib. Controls were not individually matched but were selected to represent the ’standard-care’ population without the specific exposure of interest. We acknowledge that the dasatinib group inherently comprised more high-risk patients. The use of this non-dasatinib control group is suitable as it establishes a baseline rate of AEs from the underlying disease and backbone chemotherapy. Any significant excess of AEs in the dasatinib group beyond this baseline can thus be more confidently attributed to the drug. We addressed the inherent risk disparity through stratified analysis by treatment phase and by presenting genetic risk profiles.

Inclusion criteria

Children aged 1–18 years with ALL, treated with or without dasatinib.

Exclusion criteria

Use of other targeted therapies that may interfere with outcome assessment; intolerance to dasatinib; discontinuation or incomplete treatment.

Research methods

Dasatinib regimen

Dasatinib was administered orally at 80 mg/m²/day, starting as early as possible upon Ph⁺ ALL diagnosis and continuing through maintenance therapy.

Induction therapy

• PVDL regimen: prednisone [45 mg/m²/day, oral administration (PO), tid], dexamethasone (8 mg/m²/day, PO, bid for intermediate/high-risk groups), vincristine [1.5 mg/m², intravenous injection (IV), max 2.0 mg], polyethylene glycol (PEG)-asparaginase [2,000 U/m², intramascular injection (IM)/IV], daunorubicin (25 mg/m², IV), and bortezomib (1.3 mg/m², IV for intermediate/high-risk groups).
• CAT regimen: cyclophosphamide (1,000 mg/m², IV), cytarabine [50 mg/m², subcutaneous injection (SC)/IV, q12h], and mercaptopurine (40 mg/m², PO, qd).

Maintenance therapy

• Interim phase: dexamethasone (8 mg/m²/day, PO, bid), daunorubicin (25 mg/m², IV), vincristine (1.5 mg/m², IV), and PEG-asparaginase (2,000 U/m², IM/IV).
• Reinduction: dexamethasone (8 mg/m²/day, bid), vincristine (1.5 mg/m², IV), cytarabine (2 g/m², IV, q12h), and PEG-asparaginase (2,000 U/m², IM/IV).
• Maintenance: cyclophosphamide (300 mg/m², IV), vincristine (1.5 mg/m², IV), cytarabine (300 mg/m², IV), dexamethasone (8 mg/m²/day, PO, bid), methotrexate (25 mg/m², PO), and mercaptopurine (50 mg/m²/day, PO, qd).

Adverse reaction assessment

AEs were actively identified by trained study personnel through a comprehensive review of electronic medical records, including laboratory data, physician and nursing notes, medication records, and imaging reports (e.g., echocardiograms). Each identified AE was graded according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0 (8) and categorized based on World Health Organization (WHO) terminology.

Genetic testing

RNA sequencing (RNA-seq) was performed at diagnosis for risk stratification and targeted therapy selection. Patients with ABL-family fusions received dasatinib.

Statistical analysis

SPSS 29.0 (IBM Corp., Armonk, NY, USA) was used for analysis. Descriptive statistics were used to summarize patient demographics and clinical characteristics. The comparability of the dasatinib and control groups at baseline was assessed using independent samples t-test for normally distributed continuous variables, Mann-Whitney U test for non-normally distributed variables, and Chi-squared or Fisher’s exact test for categorical variables. All statistical tests were two-sided, and a P value of <0.05 was considered statistically significant.

Results

Baseline characteristics

The study included 144 dasatinib-treated and 130 control patients (109 in induction, 165 in maintenance) (Table 1).

Adverse reactions

Maintenance phase

Dasatinib-treated children had higher rates of grade 1–3 thrombocytopenia and anemia (P<0.05). One case of grade 4 thrombocytopenia occurred (no statistical significance) (Table 2).

Induction phase

During neutropenic induction, dasatinib increased grade 1–3 thrombocytopenia (P<0.05) (Table 3). In non-neutropenic induction, only grade 2 thrombocytopenia differed significantly (P<0.05) (Table 4).

Genetic findings

• BCR-ABL1⁺ predominates (P190 subtype), often with IKZF1 lesions.
• Ph-like ALL shows alternative kinase activations (CSF1R/JAK).
• High-risk markers: TP53, IKZF1 del, C-myc rearrangements.
• Low-risk: ETV6-RUNX1 fusion (Table 5).

  Table 5

  Genetic findings

  
  

  Molecular anomaly type	Number of positive cases	Keyconcomitant anomaly
  BCR-ABL1 (P190/P210)	12	IKZF1 deletion/CDKN2A mutation
  TCF3-PBX1	4	E2A-PBX1 fusion
  ETV6-RUNX1	3	–
  STIL-TAL1	3	NOTCH1, CDKN2A mutation
  C-myc breakage	3	High-risk characteristics
  Ph-like (kinase fusion)	4	CSF1R, JAK1, CRLF2 abnormal
  IKZF1 deletion	5	Frequently associated with BCR-ABL1
  TP53 mutation	3	Complex karyotype with associated therapy resistance

Imaging findings

In 86 imaging reports (61 dasatinib, 25 control), PE (8.20%), pericardial effusion (4.92%), and tricuspid regurgitation (9.84%) were more common in the dasatinib group (Table 6).

Discussion

Pulmonary toxicity is a unique adverse reaction associated with dasatinib, with the most commonly reported pulmonary toxicities including PE, PAH, pulmonary edema, interstitial lung disease, pneumonia, and chylothorax (6). The pathogenesis of PE may stem from the inhibition of platelet-derived growth factor receptor (PDGFR) expression in pericytes, which are involved in regulating angiogenesis. This mechanism may also be related to the inhibition of Yes kinase and SRC kinase, as these kinases regulate cell adhesion to maintain pleural epithelial stability.

Research has found (6) that PAH is associated with long-term use of dasatinib, and this correlation is more pronounced in patients with PE. As of December 31, 2017, the WHO’s pharmacovigilance database (Vigibase^®) had recorded over 440 cases of PAH related to protein kinase inhibitors. Data indicate that the overall incidence of dasatinib-associated PAH is less than 1%.

The mechanism of dasatinib-induced PAH remains unclear. It may be related to multiple signaling pathways, such as SRC family kinases and the PDGF pathway, leading to endothelial dysfunction and ultimately contributing to dasatinib-associated PAH (9-13). The prescribing information for dasatinib in the United States recommends cautious use in patients with an increased risk of QT interval prolongation. In the study by Zhao et al. (4), a case was reported of a child who developed adverse reactions including PE, pericardial effusion, and PAH after using dasatinib. Echocardiography also revealed tricuspid regurgitation and pericardial effusion. After switching from dasatinib to imatinib and administering bosentan to alleviate PAH, the patient’s symptoms gradually improved. The authors concluded that the PAH may have been associated with dasatinib. In this study, a comparison of imaging findings between the dasatinib group and the control group showed that the incidence of PE, pericardial effusion, and tricuspid regurgitation was higher in the dasatinib group than in the control group. These findings suggest that dasatinib may potentially induce adverse cardiovascular effects (14). The mechanism of cardiotoxicity may be related to mitochondrial dysfunction. However, some studies suggest that alterations in kinase signaling pathways and other pathways provide a more plausible explanation for this toxicity, which likely stems from the binding effects of receptor kinases both on-target and off-target. The lack of target selectivity is associated with cardiomyocyte injury, but it also correlates with the strength of the Kd (dissociation constant) within the target.

During treatment, the concomitant use of drugs known to prolong the QT interval and potent CYP3A4 inhibitors should be avoided, as they may increase drug accumulation and lead to severe cardiotoxicity. Particular caution is required for patients receiving dasatinib in combination with other cardiotoxic agents (15-17).

In this study, it was also observed that during the maintenance phase (neutropenic state), there was a statistically significant difference between the two groups in the incidence of grade 1–3 thrombocytopenia and reduced hemoglobin levels. During the induction phase (neutropenic state), a significant difference was noted between the two groups in grade 1–3 thrombocytopenia, whereas in the induction phase (non-neutropenic state), only grade 2 thrombocytopenia showed a statistically significant difference. These findings suggest that dasatinib exerts hematologic effects regardless of whether patients are in the induction or maintenance phase.

Study (18) demonstrated that dasatinib is the least safe TKIs in chronic myeloid leukemia (CML) patients, being associated with a higher risk of severe hematologic toxicity. The mechanisms underlying its hematologic toxicity may involve two key aspects: preservation of Ph-negative hematopoietic cells with compromised functionality compared to baseline levels, which represents an intrinsic characteristic of high-risk patients. Dasatinib-mediated inhibition of SRC kinase signaling pathways (e.g., Lyn, Fyn), leading to downstream suppression of platelet aggregation and megakaryopoiesis (19,20). SRC kinases play a critical role in erythropoiesis, as well as B-cell and myeloid cell survival. Furthermore, dasatinib may induce apoptosis in human erythrocytes by altering calcium ion channel flux and cell membrane permeability (21-23).

The underlying mechanisms of dasatinib-induced hepatotoxicity remain incompletely understood. Both direct and indirect mitochondrial toxicity may play significant roles in its pathogenesis. Additionally, TKIs therapy upregulates bile acid synthesis and further alters bile acid uptake and excretion processes.

Analysis of the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database indicates that dasatinib is associated with a higher risk of nephrotoxicity—particularly proteinuric glomerulopathy—compared to other TKIs (24). Skin toxicity represents a common non-hematologic adverse effect of TKIs. Pooled data from one Phase I and five Phase II clinical trials (n=911 patients) (6) demonstrate an overall cutaneous AE incidence of ~35% with dasatinib. Notably, rash occurrence was higher in accelerated-phase (22%) or chronic-phase CML patients (13–27%) than in those with myeloid (11–14%) or lymphoid blast crisis (15–17%). Dasatinib-associated gastrointestinal bleeding shows significant correlations with female sex and age >60 years (25). As this retrospective study relied on incomplete AE documentation, accurate data on cutaneous toxicity and gastrointestinal bleeding could not be obtained.

Genetic testing provides critical guidance for both targeted therapy selection and prognostic stratification in hematologic malignancies. The presence of BCR-ABL1 fusion indicates sensitivity to TKIs, while Ph-like ALL may benefit from JAK inhibitors or ABL-class inhibitors such as dasatinib. NOTCH1 mutations warrant consideration for experimental γ-secretase inhibitor therapy. Prognostically, high-risk features include TP53 mutations, IKZF1 deletions, and C-myc rearrangements; intermediate-risk markers comprise TCF3-PBX1 and STIL-TAL1 fusions; and ETV6-RUNX1 fusion defines a low-risk subgroup. Notably, RNA sequencing coverage variability necessitates confirmatory whole-exome sequencing for comprehensive genomic profiling. Patients harboring high-risk genetic alterations such as MEF2D rearrangements or TCF3-HLF fusion should be upclassified to higher-risk categories and prioritized for targeted therapeutic interventions when clinically feasible. These findings underscore the importance of integrating molecular diagnostics into clinical decision-making to optimize therapeutic strategies and risk-adapted management.

Conclusions

In conclusion, our study demonstrates that dasatinib treatment in pediatric ALL is associated with AEs similar to those observed in adult populations, including PE, pericardial effusion, thrombocytopenia, and anemia. These findings underscore the necessity for rigorous monitoring of cardiovascular, respiratory, and hematologic parameters in children receiving dasatinib therapy to enable early detection and timely management of adverse effects, thereby optimizing treatment regimens and minimizing toxicity. However, this study has several limitations, including a small sample size and incomplete laboratory data for patients in the maintenance phase (neutropenic period) due to outpatient follow-up constraints. Further large-scale prospective studies are warranted to validate these observations and establish more comprehensive safety profiles for dasatinib in pediatric ALL.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-403/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-403/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-403/prf

Funding: This study was supported by the Joint Program on Health Science & Technology Innovation of Hainan Province (No. WSJK2024QN119); the JINYE ZHONGZI Project from Shanghai Children’s Medical Center-Hai Nan (SCMC-HN) (No. JYZZ-YJ-05); and Special Project for Hospital Pharmacy High-Quality Development Research Program, Institute of Hospital Management, National Health Commission, 2024 (No. NIHAZX202434).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-403/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University (No. SCMCIRB-K2024123-1). Individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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