Abstract
A 10-year-old female with osteoblastic osteosarcoma developed life-threatening cisplatin-induced myelosuppression (grade IV neutropenia/thrombocytopenia) following the eighth cycle of MAP chemotherapy. Critical pharmacological findings include a cumulative cisplatin dose of 720 mg/m2exceeding the pediatric safety threshold of 400 mg/m2. The CYP3A5*1/*1 genotype prolonged the half-life of cisplatin to 8.2 h. Cisplatin-specific biomarkers included serum magnesium 1.2 mg/dL and urinary N-acetyl-β-D-glucosaminidase 48 U/L. Targeted interventions (G-CSF, romiplostim, meropenem) led to hematological recovery within 14 days. This case implicates cisplatin overdose with impaired metabolic clearance as the primary toxicity mechanism.
1 Introduction
Osteosarcoma chemotherapy regimens cause myelosuppression in>80%of pediatric patients. Cisplatin is the primary myelotoxic agent in the MAP regimen, with severe (grade 3–4) cytopenia directly correlated to cumulative dose (400 mg/m2) (; ). This case of cisplatin-induced myelosuppression was managed per established guidelines (; ), emphasizing targeted interventions.
2 Case presentation
2.1 Clinical history
A 10-year-old girl presented with left knee pain. Imaging revealed a destructive lesion in the left proximal tibial metaphysis with periosteal reaction (Figures 1A,B). Biopsy confirmed osteoblastic osteosarcoma. The patient had no significant prior medical history, no family history of hematologic disorders or cancer, and no notable psychosocial stressors. Genetic testing was negative for inherited bone marrow failure syndromes.
FIGURE 1
2.2 Treatment timeline
The treatment timeline is summarized in Table 1.
TABLE 1
| Phase | Regimen | Duration |
|---|---|---|
| Neoadjuvant | Pirarubicin 40 mg/m2+Cisplatin 80 mg/m2 | Sep–December 2023 (2 cycles) |
| Surgery | Tumor resection + endoprosthesis | Aug 2024 |
| Adjuvant | Pirarubicin/Cisplatin×4 cycles | Sep–November 2024 |
| Adjuvant | Epirubicin 60 mg/m2/Cisplatin×2 cycles | Dec 2024–January 2025 |
| Adjuvant | HD-MTX 10 g/m2/Cisplatin×2 cycles | Feb 2025 |
Treatment timeline.
2.3 Treatment and toxicity timeline summary
The chronological course of treatment, onset of critical toxicity, interventions, and recovery is summarized in Table 2.
TABLE 2
| Time period | Treatment phase/Event | Regimen/Key findings | Interventions |
|---|---|---|---|
| Sep 2023 - December 2023 | Neoadjuvant Chemotherapy | 2 cycles of Pirarubicin 40 mg/m2 + Cisplatin 80 mg/m2 | - |
| Aug 2024 | Surgery | Tumor resection + endoprosthesis | - |
| Sep 2024 - November 2024 | Adjuvant Chemotherapy (Cycles 1–4) | Pirarubicin/Cisplatin ×4 cycles | - |
| Dec 2024 - January 2025 | Adjuvant Chemotherapy (Cycles 5–6) | Epirubicin 60 mg/m2/Cisplatin ×2 cycles | - |
| Feb 2025 | Adjuvant Chemotherapy (Cycles 7–8) | HD-MTX 10 g/m2/Cisplatin ×2 cycles | - |
| Feb 2025 | Onset of Myelosuppression Crisis | Fever (39.5 °C), gingival bleeding; WBC 0.8 × 109/L; ANC 0.2 × 109/L; Plt 22 × 109/L | Initiation of G-CSF, romiplostim, meropenem, Mg sulfate |
| Feb 2025 | Initial Recovery | ANC 0.8 × 109/L; Afebrile | Continued supportive care |
| Feb 2025 | Hematological Recovery | Full hematological recovery (ANC and Plt > safety thresholds) | Discontinuation of most interventions |
| Mar 2025 | Regimen Modification | - | Cisplatin dose reduction (30%), prophylactic amifostine, switch to liposomal doxorubicin |
Summary of treatment timeline, toxicity onset, interventions, and recovery.
Physical examination revealed fever, pallor, gingival bleeding, and ecchymoses. No hepatosplenomegaly, lymphadenopathy, or other systemic abnormalities were noted.
2.4 Cisplatin-specific toxicity indicators
Creatinine clearance:46 mL/min/1.73 m2 (40%below baseline).
Serum magnesium:1.2 mg/dL.
Serum malondialdehyde:8.2 μmol/L (300%above normal).
Glutathione peroxidase:28 U/mL (65%below baseline) ().
Urinary NAG:48 U/L.
Pharmacogenetic testing:
CYP3A5:*1/*1 (expresser)→reduced cisplatin clearance.
GSTP1: c.313A>G (Ile105Val) variant→impaired detoxification ().
The attribution of myelosuppression to cisplatin was based on the temporal relationship with administration, cumulative dose exceeding safety thresholds, pharmacogenetic susceptibility (CYP3A51/*1), and supportive biomarkers (hypomagnesemia, elevated malondialdehyde, urinary NAG). Alternative causes such as infection or other drug-induced myelotoxicity were ruled out through serial cultures and drug history review.
2.5 Management protocol
The detailed management protocol is outlined in Table 3.
TABLE 3
| Intervention | Dose/Regimen | Duration | Rationale |
|---|---|---|---|
| G-CSF (filgrastim) | 5 μg/kg/day SC | ANC>1.0 | Counteract neutropenia |
| Romiplostim | 10 μg/kg/week SC | Plt>100 | Target thrombocytopenia |
| Meropenem | 20 mg/kg q8h IV | Afebrile 48h | Manage febrile neutropenia |
| Magnesium sulfate | 0.3 mEq/kg/day IV | Mg > 1.8 | Correct hypomagnesemia |
Cisplatin toxicity-targeted interventions.
2.6 Outcomes
Day 5: ANC 0.8 × 109/L, afebrile.
Day 14: Full hematological recovery.
Subsequent modifications:
Cisplatin dose reduction (30%based on CYP3A5 status).
Prophylactic amifostine (740 mg/m2 pre-cisplatin) ().
Switch to liposomal doxorubicin.
3 Discussion
3.1 Mechanisms of cisplatin myelotoxicity
①DNA Damage: Cisplatin-DNA adducts↑8.7-fold in CD34+cells ().
②Mitochondrial Dysfunction: ATP production↓72%in BMSCs(p < 0.001) ().
③Metabolic Impairment: CYP3A5 expressers show 3.2×higher cisplatin plasma AUC(p = 0.002) ().
3.2 Pharmacogenomic risk stratification
CYP3A5*1/*1:4.2-fold increased risk of grade 4 myelosuppression (95%CI 2.8–6.3).
GSTP1 Ile105Val:2.9×higher adduct formation (p = 0.01).
TPMT*3A:4.1×increased hematotoxicity risk (p < 0.001) ().
3.3 Evidence-based cisplatin dose adjustment
Proposed algorithm for pediatric patients:
Pre-treatment genotyping (CYP3A5/GSTP1/TPMT).
Baseline dose = 100 mg/m2/cycle.
Dose modifiers:
CYP3A5 expresser:×0.7 (Table 4).
TABLE 4
| Toxicity type | Cisplatin-specific approach | General approach | Advantage of targeted strategy |
|---|---|---|---|
| Myelosuppression | Romiplostim + CYP3A5-guided dosing | Platelet transfusion | 68% reduction in transfusion needs () |
| Nephrotoxicity | Amifostine + Mg monitoring | Hydration only | 54% lower grade 2+ nephrotoxicity |
| Neurotoxicity | Duloxetine prophylaxis | Gabapentin PRN | 3.2× lower neuropathy incidence () |
Cisplatin-Specific vs General Interventions.
eGFR<90 mL/min:×0.8.
GSTP1 variant:×0.85.
Cumulative cap:400 mg/m.2
3.4 Comparative toxicity management
This report is based on a single case, which limits the generalizability of the findings. However, the integration of pharmacogenomic and biomarker data provides mechanistic insights that may be relevant to other pediatric patients receiving high-dose cisplatin.
4 Conclusion
This case establishes high-dose cisplatin with pharmacogenomic susceptibility as the definitive cause of life-threatening myelosuppression. Critical management innovations include:
Preemptive genotyping (CYP3A5/GSTP1) for risk stratification.
Cisplatin-specific biomarkers for early toxicity detection.
Romiplostim as superior to transfusion for cisplatin-induced thrombocytopenia.
Statements
Data availability statement
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/supplementary material.
Ethics statement
The studies involving humans were approved by the Ethics Committee of Ziyang Central Hospital, Ziyang, Sichuan, China. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin. Written informed consent was obtained from the individual(s), and minor(s)’ legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.
Author contributions
CD: Writing – original draft, Writing – review and editing. YoZ: Writing – original draft. YaZ: Writing – original draft. YD: Writing – original draft.
Funding
The author(s) declare that no financial support was received for the research and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Summary
Keywords
cisplatin-induced myelosuppression, osteosarcoma, pharmacogenomics, CYP3A5, toxicity monitoring, pediatric oncology
Citation
Dai C, Zhang Y, Zhang Y and Dong Y (2025) Case Report: Life-threatening cisplatin-induced myelosuppression in pediatric osteosarcoma: molecular mechanisms, pharmacogenomic profiling, and targeted clinical management. Front. Pharmacol. 16:1668180. doi: 10.3389/fphar.2025.1668180
Received
17 July 2025
Accepted
15 September 2025
Published
30 September 2025
Volume
16 - 2025
Edited by
Debasish Bandyopadhyay, The University of Texas Rio Grande Valley, United States
Reviewed by
Fabián Olazarán, Universidad Autónoma de Tamaulipas, Mexico
Yuanjing Ding, Jinan Central Hospital, China
Updates
Copyright
© 2025 Dai, Zhang, Zhang and Dong.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Chuanqiang Dai, 59490003@qq.com
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.