Front. Pharmacol. Frontiers in Pharmacology Front. Pharmacol. 1663-9812 Frontiers Media S.A. 1668180 10.3389/fphar.2025.1668180 Pharmacology Case Report Case Report: Life-threatening cisplatin-induced myelosuppression in pediatric osteosarcoma: molecular mechanisms, pharmacogenomic profiling, and targeted clinical management Dai et al. 10.3389/fphar.2025.1668180 Dai Chuanqiang 1 2 * Zhang Youshu 1 2 Zhang Yao 1 2 Dong Yao 1 2 1 Orthopedics, West China Hospital of Sichuan University-Ziyang Hospital, Ziyang, China 2 Orthopedics, Ziyang Central Hospital, Ziyang, China

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

 *Correspondence: Chuanqiang Dai, 59490003@qq.com 30 09 2025 2025 16 1668180 17 07 2025 15 09 2025 Copyright © 2025 Dai, Zhang, Zhang and Dong. 2025 Dai, Zhang, Zhang and Dong

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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.

 cisplatin-induced myelosuppression osteosarcoma pharmacogenomics CYP3A5 toxicity monitoring pediatric oncology section-at-acceptance Pharmacology of Anti-Cancer Drugs 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) (Harrison et al., 2021; Bielack et al., 2022). This case of cisplatin-induced myelosuppression was managed per established guidelines (Freifeld et al., 2024; Smith et al., 2023), 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.

Pre-treatment imaging of the left proximal tibia. (A) Anteroposterior radiograph showing a destructive lesion with periosteal reaction. (B) Coronal CT image confirming osteolytic destruction and soft tissue involvement.

X-ray images show a side-by-side comparison of a knee joint. Image A displays a standard X-ray with clear bone structures, including the femur, tibia, and knee joint. Image B is a CT scan of the same area, highlighting internal bone detail with different contrast levels. Both images focus on the left knee. 2.2 Treatment timeline

The treatment timeline is summarized in Table 1.

Treatment timeline.

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
2.3 Treatment and toxicity timeline summary

The chronological course of treatment, onset of critical toxicity, interventions, and recovery is summarized in Table 2.

Summary of treatment timeline, toxicity onset, interventions, and recovery.

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

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) (Park et al., 2023).

Urinary NAG:48 U/L.

Pharmacogenetic testing:

CYP3A5:*1/*1 (expresser)→reduced cisplatin clearance.

GSTP1: c.313A>G (Ile105Val) variant→impaired detoxification (Oldenburg et al., 2024).

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.

Cisplatin toxicity-targeted interventions.

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
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) (Santos et al., 2023).

Switch to liposomal doxorubicin.

 3 Discussion 3.1 Mechanisms of cisplatin myelotoxicity

①DNA Damage: Cisplatin-DNA adducts↑8.7-fold in CD34+cells (Fu et al., 2024).

②Mitochondrial Dysfunction: ATP production↓72%in BMSCs(p < 0.001) (Marullo et al., 2023).

③Metabolic Impairment: CYP3A5 expressers show 3.2×higher cisplatin plasma AUC(p = 0.002) (Karol et al., 2024).

 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) (Relling and Evans, 2023).

 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).

Cisplatin-Specific vs General Interventions.

Toxicity type Cisplatin-specific approach General approach Advantage of targeted strategy
Myelosuppression Romiplostim + CYP3A5-guided dosing Platelet transfusion 68% reduction in transfusion needs (Soff et al., 2023)
Nephrotoxicity Amifostine + Mg monitoring Hydration only 54% lower grade 2+ nephrotoxicity
Neurotoxicity Duloxetine prophylaxis Gabapentin PRN 3.2× lower neuropathy incidence (Majithia et al., 2024)

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.

 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.

 Generative AI statement

The author(s) declare that no Generative AI was used in the creation of this manuscript.

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