1. INTRODUCTION
Cancer therapy–induced thrombocytopenia (CTIT) results from antineoplastic treatment in patients with cancer. This condition encompasses various forms of therapy-related thrombocytopenia, including the commonly observed chemotherapy-induced thrombocytopenia, immune checkpoint inhibitor (ICI)–induced thrombocytopenia, targeted therapy–induced thrombocytopenia, and radiotherapy-induced thrombocytopenia. CTIT is one of the most common adverse effects of cancer therapies. It is characterized by a pathological decrease in the peripheral platelet count (PLT) resulting from the suppression of megakaryocyte production in the bone marrow caused by multiple anticancer modalities.1 The overall incidence of CTIT can reach 9.7%, significantly affecting patients’ quality of life and imposing a substantial burden on families and society.2
Eltrombopag is an orally administered, non-peptide, small-molecule thrombopoietin receptor agonist (TPO-RA). Its mechanism of action involves mimicking endogenous thrombopoietin by activating the thrombopoietin receptor (TPO-R), thereby promoting the proliferation and maturation of bone marrow megakaryocytes and enhancing platelet production.3 Currently, eltrombopag has demonstrated favorable clinical efficacy in the treatment of thrombocytopenia associated with chronic immune thrombocytopenia and hepatitis C virus–related cirrhosis.4 Although studies on eltrombopag in CTIT are limited, available evidence suggests its potential therapeutic value. Kellum et al found that eltrombopag significantly increased PLT in patients with advanced solid tumors undergoing combination chemotherapy with carboplatin and paclitaxel, with good tolerability.5 Similarly, Chawla et al6 observed a positive effect of eltrombopag on the elevation of PLT. These findings provide preliminary evidence supporting the use of eltrombopag in managing CTIT. However, both studies had relatively small sample sizes, and the primary endpoint was not achieved in the study by Chawla et al,6 limiting the generalizability and statistical power of the results.
This study aimed to evaluate the real-world efficacy and safety of eltrombopag in the treatment of CTIT, with a particular focus on the relationship between the timing and duration of eltrombopag administration and changes in PLT, bleeding events, and the occurrence of adverse drug reactions.
2. METHODS
2.1. Study design
This study included 2101 patients with CTIT receiving eltrombopag at a starting dose of 50 mg once daily, which was subsequently adjusted based on PLT. If the PLT reached ≥250 × 109/L, the dose was reduced or discontinued according to routine clinical practice; otherwise, treatment was continued for either 7 or 14 days. Data were collected from the oncology or hematology departments of 5 provinces and municipalities in China between March 2024 and February 2025. This study was approved by the Medical Ethics Committee of Henan Cancer Hospital (Approval No. 2024-139-001), and the requirement for informed consent was waived.
2.2. Inclusion and exclusion criteria
The inclusion criteria were as follows: age ≥18 years; histologically or cytologically confirmed malignant solid tumors (including gynecologic, gastrointestinal, lung, or head and neck tumors) treated with chemotherapy, targeted therapy, immunotherapy, or radiotherapy. Hematological malignancies were not included; peripheral PLT of <100 × 109/L before treatment; oral administration of eltrombopag olamine tablets at 50 mg once daily. The exclusion criteria were as follows: age <18 years; use of other TPO-RAs; presence of other thrombocytopenic conditions, such as aplastic anemia, radiation sickness, immune thrombocytopenia, hypersplenism, or bone marrow infiltration by tumor cells; use of non-oncologic drugs known to cause thrombocytopenia, such as sulfonamides; pseudothrombocytopenia due to EDTA anticoagulant; coagulopathy or a history of thrombotic events within the past 2 months; incomplete records or missing key information.
2.3. Efficacy evaluation
PLT were assessed on day 7 or 14 of treatment. Efficacy was evaluated using the following criteria: overall response (OR) rate, the proportion of patients whose post-treatment PLT reached ≥50 × 109/L; complete response (CR) rate, the proportion of patients whose post-treatment PLT reached ≥100 × 109/L; and high response rate, the proportion of patients whose PLT increased by ≥100% from baseline. Additionally, adverse events occurring during the treatment period were classified and recorded based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.0. Particular attention was paid to the proportion of patients who experienced bleeding events during treatment.
2.4. Statistical analysis
Continuous variables were expressed as mean ± standard deviation, and comparisons between groups were performed using independent sample t tests. Categorical variables were presented as frequencies and percentages (%), and differences between groups were assessed using the Chi-square test or Fisher exact test, where appropriate. Given the non-continuous time-point nature of PLT observations, a weighted generalized linear model was used to treat days 7 and 14 post-treatment as independent observation points. This approach was used to compare efficacy indicators (eg, OR and CR rates) between groups and evaluate the differences in treatment efficacy among various patient subgroups at specific time points. All data analyses were conducted using R software (version 4.3.2). Statistical significance was defined as a 2-sided p value of <0.050.
3. RESULTS
3.1. Baseline characteristics
Among the 2101 patients included in the study, 1279 were in the 7-day group, and 822 were in the 14-day group. The baseline characteristics of the patients are summarized in Table 1. Of these, 1015 (48.3%) were male, and 1086 (51.7%) were female, with a mean age of 57.9 ± 11.7 years and a mean body weight of 59.6 ± 8.53 kg. The mean baseline PLT was (37.0 ± 20.1) × 109/L. Patients with stage I tumors were excluded from the study. A total of 807 patients (38.4%) had metastatic disease, and 707 patients (33.7%) received concurrent radiotherapy. The most common tumor types were lung cancer (n = 624, 29.7%) and gastrointestinal cancers (n = 744, 35.4%), including colorectal, liver, pancreatic, esophageal, and bile duct cancers. Other tumor types included malignancies of the female reproductive system (eg, breast, cervical, and ovarian cancers), malignant melanoma, and head and neck cancers (eg, nasopharyngeal and laryngeal cancers). Additionally, 894 patients (42.6%) had comorbid hypertension, and 230 patients (10.9%) had hepatic dysfunction. The other comorbidities included diabetes mellitus and renal diseases.
Table 1.
Baseline characteristics of patients in the 7- and 14-d groups.
| Variable | 7-Day | 14-Day | Total |
|---|---|---|---|
| (n = 1279) | (n = 822) | (n = 2101) | |
| Age (y) | 57.8 ± 12.0 | 58.2 ± 11.3 | 57.9 ± 11.7 |
| Male, n (%) | 595 (46.5) | 420 (51.1) | 1015 (48.3) |
| Female, n (%) | 684 (53.5) | 402 (48.9) | 1086 (51.7) |
| Body weight (kg) | 59.3 ± 8.51 | 60.1 ± 8.55 | 59.6 ± 8.53 |
| Platelet count before treatment (×109/L) | 40.9 ± 19.5 | 31.0 ± 19.5 | 37.0 ± 20.1 |
| Tumor type, n (%) | |||
| Lung cancer | 364 (28.5) | 260 (31.6) | 624 (29.7) |
| Gastrointestinal cancer | 442 (34.6) | 302 (36.7) | 744 (35.4) |
| Breast cancer | 160 (12.5) | 89 (10.8) | 249 (11.9) |
| Ovarian cancer | 132 (10.3) | 69 (8.4) | 201 (9.6) |
| Others | 181 (14.2) | 102 (12.4) | 283 (13.5) |
| Tumor metastasis, n (%) | |||
| No | 786 (61.5) | 508 (61.8) | 1294 (61.6) |
| Yes | 493 (38.5) | 314 (38.2) | 807 (38.4) |
| Tumor stage, n (%) | |||
| II | 425 (33.2) | 261 (31.8) | 686 (32.7) |
| III | 600 (46.9) | 403 (49.0) | 1003 (47.7) |
| IV | 254 (19.9) | 158 (19.2) | 412 (19.6) |
| Combined radiotherapy, n (%) | 273 (21.3) | 434 (52.8) | 707 (33.7) |
| Comorbidities, n (%) | |||
| Hepatic dysfunction | 148 (11.6) | 82 (10.0) | 230 (10.9) |
| Diabetes mellitus | 234 (18.3) | 183 (22.3) | 417 (19.8) |
| Hypertension | 561 (43.9) | 333 (40.5) | 894 (42.6) |
| Renal diseases | 58 (4.5) | 31 (3.8) | 89 (4.2) |
| Others | 278 (21.7) | 193 (23.5) | 471 (22.4) |
PLT = platelet count.
Data are presented as mean ± standard deviation for continuous variables and n (%) for categorical variables.
3.2. Efficacy analysis
The OR rates were 83.4% on day 7 and 87.8% on day 14, with a significantly higher rate observed on day 14 (p = 0.006). The CR rates were 28.5% in the 7-day group and 37.6% in the 14-day group, with a higher CR rate observed in the 14-day group (p < .001) (Table 2). However, when analyzed using a weighted generalized linear model, the differences in OR and CR rates between the 2 groups were not statistically significant (Table 3).
Table 2.
Comparison of platelet OR and CR rate between the 7- and 14-d groups.
| 7-Day | 14-Day | |||
|---|---|---|---|---|
| (n = 1279) | (n = 822) | χ 2 | p Value | |
| OR rate, n (%) | 1067 (83.4) | 722 (87.8) | 7.696 | 0.006 |
| CR rate, n (%) | 365 (28.5) | 309 (37.6) | 18.823 | <.001 |
CR = complete response, OR = overall response.
OR was defined as a post-treatment platelet count ≥50 × 109/L, and CR was defined as a post-treatment platelet count ≥100 × 109/L. Differences between groups were assessed using the Chi-square test.
Table 3.
Weighted GLM analysis of OR and CR rate.
| Model | Coefficient estimate | Std. error | Z Value | p Value | |
|---|---|---|---|---|---|
| OR rate | 1 | 0.361 | 0.114 | 3.17 | 0.002 |
| 2 | 0.357 | 0.114 | 3.12 | 0.002 | |
| 3 | −0.006 | 0.120 | −0.05 | 0.962 | |
| CR rate | 1 | 0.411 | 0.085 | 4.85 | <.001 |
| 2 | 0.407 | 0.085 | 4.79 | <.001 | |
| 3 | −0.033 | 0.095 | −0.35 | 0.726 |
Coefficient estimate = estimated regression coefficient, CR = complete response, GLM = generalized linear model, OR = overall response, Std. error = standard error, Z value = Z statistic.
Weighted generalized linear models were used to evaluate the association between treatment time point and platelet response. Model 1 included treatment time point only; model 2 was additionally adjusted for age, body weight, and sex; model 3 was further adjusted for disease status, tumor metastasis, and radiotherapy.
3.3. Subgroup analysis
The severity of thrombocytopenia was graded as follows: grade 1: 75 ≤ PLT < 100 × 109/L; grade 2: 50 ≤ PLT < 75 × 109/L; grade 3: 25 ≤ PLT < 50 × 109/L; and grade 4: PLT < 25 × 109/L.
In the 7-day group, the OR rate in patients with baseline grade 4 thrombocytopenia was 46.6%, whereas the OR rate in patients with grade 3 thrombocytopenia reached 88.7%, indicating that patients with higher baseline platelet levels exhibited a higher short-term response. In the 14-day group, the OR rate in patients with grade 4 increased to 82.8%. Chi-square analysis showed a statistically significant difference in OR rates between the 2 groups in patients with grade 4 thrombocytopenia (χ2 = 89.456, p < .001). Regarding CR rates, only 4.2% of patients with grade 4 thrombocytopenia achieved a complete response on day 7, compared with 77.3% of patients with grade 1 thrombocytopenia. In the 14-day group, the CR rate in patients with grade 3 thrombocytopenia reached 30.4%, whereas that in patients with grade 4 improved markedly from 4.2% to 44.9%. The Chi-square test indicated a highly significant difference in CR rates between the 2 groups in patients with grade 4 thrombocytopenia (χ2 = 123.22, p < .001). Differences were also significant but less pronounced in patients with grade 3 and those with grade 2 thrombocytopenia (χ2 = 14.560, p < .001; χ2 = 5.102, p =0.024), suggesting that extended treatment duration provides meaningful benefit in patients with lower baseline PLT. Similarly, the high response rate also demonstrated time-point dependency. In the 7-day group, the high response rate in patients with grade 3 thrombocytopenia was 49.2%, whereas it was only 4.5% in those with grade 1. In the 14-day group, the high response rate in patients with grade 4 increased significantly to 93.6% (Table 4).
Table 4.
Comparison of platelet response outcomes in the 7- and 14-d group across baseline thrombocytopenia grades.
| Thrombocytopenia | 7-Day (n = 1279) | 14-Day (n = 822) | χ2 | p Value | |
|---|---|---|---|---|---|
| Grade | |||||
| OR rate, n (%) | 1 | - | - | - | - |
| 2 | - | - | - | - | |
| 3 | 524/591 (88.7) | 299/336 (89.0) | 0.002 | 0.967 | |
| 4 | 122/262 (46.6) | 299/361 (82.8) | 89.456 | <.001 | |
| CR rate, n (%) | 1 | 51/66 (77.3) | 15/46 (32.6) | 20.535 | <.001 |
| 2 | 190/360 (52.8) | 30/79 (38.0) | 5.102 | 0.024 | |
| 3 | 113/591 (19.1) | 102/336 (30.4) | 14.560 | <.001 | |
| 4 | 11/262 (4.2) | 162/361 (44.9) | 123.220 | <.001 | |
| High response rate, n (%) | 1 2 |
3/66 (4.5) 89/360 (24.7) |
3/46 (6.5) 24/79 (30.4) |
0.001 0.809 |
0.976 0.368 |
| 3 | 291/591 (49.2) | 209/336 (62.2) | 13.973 | <.001 | |
| 4 | 175/262 (66.8) | 338/361 (93.6) | 73.360 | <.001 |
CR = complete response, OR = overall response.
Baseline thrombocytopenia grades were defined according to platelet count before treatment: grade 1, 75 ≤ PLT <100 × 109/L; grade 2, 50 ≤ PLT < 75 × 109/L; grade 3, 25 ≤ PLT <50 × 109/L; grade 4, PLT < 25 × 109/L.
3.4. Bleeding events
Our results showed that among patients with baseline grade 4 thrombocytopenia, the number of bleeding events increased significantly after treatment: from 6 cases (2.29%) before medication to 21 cases (8.02%) in the 7-day group, and from 8 cases (2.22%) to 43 cases (11.91%) in the 14-day group. In contrast, patients with grade 1 thrombocytopenia exhibited an opposite trend, with 1 bleeding event before treatment in both the 7-day (1.52%) and 14-day groups (2.17%), and no bleeding events after treatment. For patients with grade 3 thrombocytopenia, the number of bleeding events decreased from 11 (1.86%) before treatment to 4 (0.68%) in the 7-day group and from 3 (0.89%) to 1 (0.30%) in the 14-day group. In patients with grade 2 thrombocytopenia, 7 (1.94%) had bleeding events before treatment in the 7-day group, but none afterward. Similarly, in the 14-day group, the number decreased from 2 (2.53%) before treatment to 1 (1.27%) after treatment.
Overall, the intervention had a significant effect on the 7-day group, with post-treatment bleeding rates dropping to zero in patients with grade 1 and those with grade 2 thrombocytopenia. In the 14-day group, the bleeding rate declined further, particularly in patients with grade 1 thrombocytopenia, in whom no bleeding events occurred after treatment. These findings suggest that the intervention provides strong protective effects in patients with higher baseline PLT. However, the increased bleeding rate observed in patients with grade 4 thrombocytopenia after treatment indicates the need for further optimization of therapeutic strategies to reduce the associated risks. Detailed results are presented in Figure 1.
Figure 1.
Stratified analysis of bleeding rates before and after treatment based on baseline platelet levels.
3.5. Safety analysis
A total of 931 adverse events were reported (Table 5). The most common event was pallor, occurring in 413 cases (19.6%), followed by fatigue (156 cases, 7.4%), dizziness and headache (123 cases, 5.9%), nausea and vomiting (79 cases, 3.8%), gastrointestinal reactions (71 cases, 3.4%), bleeding (70 cases, 3.3%), bone pain (15 cases, 0.7%), thrombosis (3 cases, 0.1%), and elevated transaminases (1 case, 0.05%). In total, 143 grade 3 or 4 adverse events were recorded, primarily pallor (80 cases, 3.8%) and fatigue (34 cases, 1.6%). Other grade 3–4 adverse events included nausea and vomiting (15 cases, 0.7%), gastrointestinal reactions (8 cases, 0.4%), bleeding (5 cases, 0.2%), and dizziness and headache (1 case, 0.05%). No grade 3–4 events of bone pain, thrombosis, or elevated transaminase levels were observed.
Table 5.
Incidence of adverse events following eltrombopag treatment.
| Adverse event | n (%) | Grade 3–4, n (%) |
|---|---|---|
| Pallor | 413 (19.6) | 80 (3.8) |
| Fatigue | 156 (7.4) | 34 (1.6) |
| Dizziness and headache | 123 (5.9) | 1 (0.05) |
| Nausea and vomiting | 79 (3.8) | 15 (0.7) |
| Gastrointestinal reactions | 71 (3.4) | 8 (0.4) |
| Bleeding | 70 (3.3) | 5 (0.2) |
| Bone pain | 15 (0.7) | 0 |
| Thrombosis | 3 (0.1) | 0 |
| Elevated transaminases | 1 (0.05) | 0 |
Adverse events were classified and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Data are presented as n (%).
4. DISCUSSION
This study aimed to evaluate the efficacy and safety of oral eltrombopag in patients who underwent CTIT. The findings revealed that bleeding events nearly disappeared within 7 days of eltrombopag treatment in 60% of the patients. Patients with different baseline platelet levels demonstrated clear time-dependent improvements in OR, CR, and high response rates after eltrombopag treatment. In patients with grade 1–3 thrombocytopenia, the treatment response was typically rapid and significant within 7 days. In contrast, patients with grade 4 thrombocytopenia required a longer treatment duration to achieve meaningful clinical benefits, with notable improvements in CR and high response rates observed by day 14. Overall, eltrombopag effectively increased PLT and reduced the incidence of bleeding events. In clinical practice, treatment strategies should be tailored according to the patient’s baseline PLT to maximize therapeutic outcomes and minimize the risk of bleeding.
The mechanisms underlying the thrombocytopenia induced by different cancer treatment modalities vary. Among these, chemotherapy-induced thrombocytopenia has been well characterized. It primarily results from the suppression of hematopoietic stem cells and megakaryocytic progenitor cells by chemotherapeutic agents, thereby inhibiting platelet production, impeding megakaryocyte maturation and differentiation, and inducing excessive apoptosis in these cells.7 Certain targeted therapies, such as proteasome inhibitors (eg, bortezomib), trastuzumab emtansine (T-DM1), and PARP inhibitors, may impair the ability of mature megakaryocytes to release platelets, leading to targeted therapy–induced thrombocytopenia. The mechanisms of ICI-induced thrombocytopenia remain unclear but are potentially associated with T-cell activation and the removal of immune checkpoints. Radiation therapy induces ionization and increases free radicals, resulting in DNA damage, including double-strand breaks. This leads to apoptosis, differentiation arrest, senescence of hematopoietic stem cells, and injury to the hematopoietic microenvironment, thereby impairing hematopoiesis.
Approximately 5% to 10% of patients with solid tumors present with thrombocytopenia at initial diagnosis, and its incidence increases progressively during the treatment course.8 A complex and reciprocal interaction occurs between tumor cells and platelets, referred to as the “platelet–tumor loop.”9 Single nucleotide polymorphisms (SNPs) and mutations in genes encoding cytokines and transcription factors are the two primary contributors to thrombocytopenia in solid tumors, including lung cancer, breast cancer, ovarian cancer, and colorectal cancer.10 The -31T>C SNP in the interleukin-1β (IL-1β) gene is upregulated in solid tumors associated with thrombocytopenia.11 Although the precise mechanism by which IL-1β induces thrombocytopenia in solid tumors remains unclear, the -31T>C SNP has been shown to increase the susceptibility of these malignancies to thrombocytopenia.10 Moreover, a strong association exists between the IL-1β-31T>C SNP and Helicobacter pylori infection, and their synergistic interaction significantly elevates the risk of bleeding complications in gastric cancer.9,12,13 Interleukin-6 (IL-6) is also involved in the pathogenesis of thrombocytopenia and paraneoplastic thrombocytosis. The IL-6-174 G/C SNP has been reported in several malignancies, including lung cancer, colorectal cancer, gastric cancer, and ovarian cancer.9,11,14,15 This genetic polymorphism is also associated with poor prognosis, as it may trigger the production of antiplatelet antibodies and elevate the risk of thrombocytopenia.10 In certain cases, tumors may also produce autoantibodies targeting platelet glycoproteins, resulting in immune thrombocytopenia.16,17 Additionally, certain active tumor metabolites suppress megakaryocyte differentiation and maturation.18,19
Oral TPO-RAs interact with the transmembrane domain of the human TPO-R, triggering downstream signaling cascades that promote the proliferation and differentiation of myeloid progenitor and megakaryocytic cells.20–22 Notably, TPO-RAs do not share homologous sequences with endogenous thrombopoietin (TPO), thus preventing cross-reactivity and the formation of neutralizing antibodies. TPO-RAs significantly increase PLT in patients with CTIT and effectively reduce the incidence of grade 3/4 thrombocytopenia.23,24 Eltrombopag, a small-molecule TPO-RA, activates the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway by binding to the transmembrane domain of the TPO receptor. It promotes the proliferation and differentiation of megakaryocytic progenitor cells, improves the bone marrow microenvironment, suppresses inflammation, modulates the immune system, and reduces the production of antiplatelet autoantibodies. Additionally, it enhances regulatory T-cell activity and increases transforming growth factor-β1 levels, potentially restoring immune tolerance.25 In a phase II clinical trial, eltrombopag demonstrated a lower incidence of grade 3/4 thrombocytopenia compared with placebo in patients receiving gemcitabine alone or gemcitabine combined with cisplatin/carboplatin for solid tumors. The incidence was reduced in the combination therapy group (77 patients vs 100%) and the monotherapy group (36 patients vs 42%). Among patients undergoing combination chemotherapy, the mean recovery time from the platelet nadir was 8 days in the eltrombopag group and 15 days in the placebo group. Eltrombopag also shortened the recovery time in patients receiving gemcitabine-based regimens and reduced chemotherapy delays or dose reductions due to thrombocytopenia.26 In another study by Zhu et al,27 153 patients with lymphoma who developed grade 3/4 thrombocytopenia after chemotherapy were enrolled to compare the clinical efficacy and safety of eltrombopag and recombinant human thrombopoietin (rhTPO) for chemotherapy-induced thrombocytopenia. The eltrombopag group showed significantly higher minimum and mean PLT on days 5, 7, and 10 than the control group. Although the time required to reach platelet thresholds of ≥50 × 109/L and ≥75 × 109/L did not differ between the groups, the PLT were significantly higher in the eltrombopag group. Furthermore, bleeding and platelet transfusion rates were significantly lower in the eltrombopag group, confirming its safety and efficacy in treating chemotherapy-induced thrombocytopenia in patients with lymphoma. A separate phase II trial evaluated eltrombopag in patients with chronic myeloid leukemia (CML) or myelofibrosis (MF) who experienced persistent thrombocytopenia during treatment with tyrosine kinase inhibitors (TKIs) or ruxolitinib.28 The median baseline PLT were 44 (3–49) × 109/L in CML and 62 (21–75) × 109/L in MF. After a median treatment duration of 18 months, 80% of patients with CML achieved a complete platelet response, with a median peak PLT of 154 (74–893) × 109/L among responders. Additionally, 5 patients were able to resume or escalate their TKI dosage, and 9 patients showed an improved disease response. These findings suggest that eltrombopag is beneficial for managing recurrent thrombocytopenia in patients with CML undergoing TKI therapy.
ICIs have demonstrated antitumor activity against various malignancies. However, ICI-induced thrombocytopenia, along with other forms of immune-related cytopenia, has been increasingly reported in the context of ICIs and cellular immunotherapies. Ito et al29 reported on a patient with advanced non–small-cell lung cancer (NSCLC) who developed refractory immune-related thrombocytopenia induced by pembrolizumab. Treatment with eltrombopag significantly improved thrombocytopenia, suggesting that it is an effective therapeutic option for refractory immune-mediated thrombocytopenia induced by pembrolizumab. Similarly, Harada et al30 described a case of an 82-year-old male with NSCLC who developed severe immune thrombocytopenia 3 weeks after the third cycle of atezolizumab. The patient was initially treated with high-dose prednisolone, intravenous immunoglobulin, and platelet transfusions but showed no clinical improvement. The addition of eltrombopag resulted in a marked recovery in the PLT, indicating its potential efficacy in managing ICI-related thrombocytopenia, which is unresponsive to conventional immunosuppressive therapies.
However, TPO-RAs may increase soluble P-selectin levels, thereby increasing the risk of thrombosis.25 Nevertheless, the current literature suggests that eltrombopag does not exhibit a higher overall incidence of thromboembolic events than other TPO-RAs, such as romiplostim. In the present study, only 3 cases of thrombotic adverse events were reported, and the incidence of hepatic dysfunction was low, indicating that eltrombopag has a favorable safety profile. Although patients with baseline PLT <25 × 109/L did not experience a reduction in bleeding events after treatment, this may be due to severe impairment of bone marrow hematopoietic function. These findings underscore the need for further optimization of therapeutic strategies in this high-risk population.
This study employed a retrospective multicenter design, enrolling 2101 patients from various regions with diverse solid tumor types. By simultaneously evaluating PLT changes on days 7 and 14 and conducting stratified analyses based on baseline platelet levels, this study further substantiated the clinical value of eltrombopag in shortening platelet recovery time and reducing bleeding events. Unlike previous studies that primarily focused on early time points or limited treatment cycles, this study compared the OR and CR rates across multiple time points. Although no statistically significant differences in platelet responses were observed between the 7- and 14-day treatment durations, patients with severely low baseline PLT required extended treatment cycles or adjunctive interventions to prevent bleeding. Overall, this study overcomes the limitations of single-center or small-sample studies by incorporating multiple time points and stratified analyses. It provides robust real-world evidence supporting the optimization of eltrombopag treatment duration and safety monitoring in patients with CTIT, laying a solid foundation for further exploration of the therapeutic potential of eltrombopag in managing CTIT.
Despite providing clinical evidence for the use of eltrombopag in CTIT in a large-scale, multicenter population, this study has several limitations. First, as a retrospective analysis lacking randomization and prospective follow-up, the heterogeneity in chemotherapy regimens and dosing may have contributed to variability in outcomes. Second, the potential impact of comorbidities, such as cardiovascular disease or a history of thrombosis, on bleeding events was not thoroughly explored. Third, although platelet responses were assessed at 2 observation time points (days 7 and 14), the study employed non-continuous, repeated measures, limiting the ability to capture dynamic changes in PLT over time. Fourth, detailed bleeding subtypes were not separately recorded owing to the retrospective design; thus, our analysis was based on the NCI-CTCAE severity grading system, which reflects overall safety but precludes granular subtype analysis.
Based on the findings and limitations of this study, future research directions should include conducting prospective randomized controlled trials to provide higher-level evidence. More in-depth subgroup analyses based on different tumor types or therapy regimens are needed to identify optimal beneficiary populations. Furthermore, exploring combination strategies in patients with severe thrombocytopenia and conducting long-term efficacy and safety studies are crucial.
Eltrombopag demonstrated favorable efficacy in the treatment of patients with CTIT. In patients with grade 3 or higher thrombocytopenia, a 7-day course of eltrombopag at 50 mg once daily significantly increased PLT and effectively reduced bleeding events. However, the incidence of bleeding remained high in patients with grade 4 thrombocytopenia, suggesting that monotherapy is insufficient. Optimized treatment strategies, such as prolonged duration, dose adjustment, or combination therapy, may be required to enhance platelet recovery and reduce bleeding risk more effectively.
ETHICAL APPROVAL
This study was approved by the Medical Ethics Committee of Henan Cancer Hospital (Approval No: 2024-139-001) and was granted a waiver of informed consent.
AUTHOR CONTRIBUTIONS
H.Z. designed the study. B.D., Y.C., H.H., Y.L., and L.Z. performed the study. B.D., L.L., and L.Z. collected data. H.Z. analyzed data. B.D. and H.Z. wrote the paper. H.Z. performed the final revision of the manuscript.
Footnotes
Conflict of interest: The authors declare that they have no conflict of interest.
To protect participant privacy, data are not publicly available but can be obtained from the corresponding author upon reasonable request.
REFERENCES
- [1].Wang Y, Ma HX, Liu TS. Meta analysis of recombinant human thrombopoietin in chemotherapy induced thrombocytopeilia. J Evid Based Med 2013;13(4):225–229. [Google Scholar]
- [2].Ren J, Lu LN, Wang G, Zhang RJ, Ma YP, Yang LH. Hematological neoplasms secondary to malignant solid tumors with radiotherapy and chemotherapy: a clinical and prognostic analysis. Journal of Experimental Hematology 2023;31(2):383–388. [DOI] [PubMed] [Google Scholar]
- [3].Erickson-Miller CL, Delorme E, Tian SS, et al. Preclinical activity of eltrombopag (SB-497115), an oral, nonpeptide thrombopoietin receptor agonist. Stem Cells 2009;27(2):424–430. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [4].Society of Chemotherapy, China Anti-Cancer Association; Committee of Neoplastic Supportive-Care, China Anti-Cancer Association. Consensus on the clinical diagnosis, treatment and prevention of cancer treatment-induced thrombocytopenia in China (2023 edition). Zhonghua Yi Xue Za Zhi 2023;103(33):2579–2590. [DOI] [PubMed] [Google Scholar]
- [5].Kellum A, Jagiello-Gruszfeld A, Bondarenko IN, Patwardhan R, Messam C, Mostafa Kamel Y. A randomized, double-blind, placebo-controlled, dose ranging study to assess the efficacy and safety of eltrombopag in patients receiving carboplatin/paclitaxel for advanced solid tumors. Curr Med Res Opin 2010;26(10):2339–2346. [DOI] [PubMed] [Google Scholar]
- [6].Chawla SP, Staddon A, Hendifar A, Messam CA, Patwardhan R, Kamel YM. Results of a phase I dose escalation study of eltrombopag in patients with advanced soft tissue sarcoma receiving doxorubicin and ifosfamide. BMC Cancer 2013;13:121. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [7].Gao A, Zhang LL, Zhong DS. Chemotherapy-induced thrombocytopenia: literature review. Discov Oncol 2023;14(1):10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [8].Yang BY. Climical recognition and management of thrombocytopenia in solid tumor. Zhonghua Yi Xue Za Zhi 2019;99(8):561–565. [DOI] [PubMed] [Google Scholar]
- [9].Catani MV, Savini I, Tullio V, et al. The “Janus Face” of platelets in cancer. Int J Mol Sci 2020;21(3):788. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [10].Ghanavat M, Ebrahimi M, Rafieemehr H, Maniati M, Behzad MM, Shahrabi S. Thrombocytopenia in solid tumors: prognostic significance. Oncol Rev 2019;13(1):413. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [11].Pooja S, Chaudhary P, Nayak LV, et al. Polymorphic variations in IL-1beta, IL-6 and IL-10 genes, their circulating serum levels and breast cancer risk in Indian women. Cytokine 2012;60(1):122–128. [DOI] [PubMed] [Google Scholar]
- [12].Xue HP, Lin B, Ni PH, Xu H, Huang G. Interleukin-1B and interleukin-1 RN polymorphisms and gastric carcinoma risk: a meta-analysis. J Gastroenterol Hepatol 2010;25(10):1604–1617. [DOI] [PubMed] [Google Scholar]
- [13].Ying HY, Yu BW, Yang Z, et al. Interleukin-1B 31 C>T polymorphism combined with Helicobacter pylori-modified gastric cancer susceptibility: evidence from 37 studies. J Cell Mol Med 2016;20(3):526–536. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [14].Hefler LA, Grimm C, Ackermann S, et al. An interleukin-6 gene promoter polymorphism influences the biological phenotype of ovarian cancer. Cancer Res 2003;63(12):3066–3068. [PubMed] [Google Scholar]
- [15].Talar-Wojnarowska R, Gasiorowska A, Smolarz B, Romanowicz-Makowska H, Kulig A, Malecka-Panas E. Clinical significance of interleukin-6 (IL-6) gene polymorphism and IL-6 serum level in pancreatic adenocarcinoma and chronic pancreatitis. Dig Dis Sci 2009;54(3):683–689. [DOI] [PubMed] [Google Scholar]
- [16].Nobuoka A, Sakamaki S, Kogawa K, et al. A case of malignant lymphoma producing autoantibody against platelet glycoprotein Ib. Int J Hematol 1999;70(3):200–206. [PubMed] [Google Scholar]
- [17].Vial G, Rivière E, Raymond AA, et al. Antigenic mimicry in paraneoplastic immune thrombocytopenia. Front Immunol 2019;10:523. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [18].Kusmartsev S, Gabrilovich DI. Effect of tumor-derived cytokines and growth factors on differentiation and immune suppressive features of myeloid cells in cancer. Cancer Metastasis Rev 2006;25(3):323–331. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [19].Liu P, Wang LL, Yu HY. Polyploid giant cancer cells: origin, possible pathways of formation, characteristics, and mechanisms of regulation. Front Cell Dev Biol 2024;12:1410637. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [20].Birocchi S, Podda GM, Manzoni M, Casazza G, Cattaneo M. Thrombopoietin receptor agonists for the treatment of primary immune thrombocytopenia: a meta-analysis and systematic review. Platelets 2021;32(2):216–226. [DOI] [PubMed] [Google Scholar]
- [21].Wang L, Gao Z, Chen XP, et al. Efficacy and safety of thrombopoietin receptor agonists in patients with primary immune thrombocytopenia: a systematic review and meta-analysis. Sci Rep 2016;6:39003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [22].Kapur R, Aslam R, Speck ER, Rebetz JM, Semple JW. Thrombopoietin receptor agonist (TPO-RA) treatment raises platelet counts and reduces anti-platelet antibody levels in mice with immune thrombocytopenia (ITP). Platelets 2020;31(3):399–402. [DOI] [PubMed] [Google Scholar]
- [23].Gurumurthy G, Kisiel F, Gurumurthy S, Gurumurthy J. Role of thrombopoietin receptor agonists in chemotherapy-induced thrombocytopenia: a meta-analysis. J Oncol Pharm Pract 2025;31(1):4–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [24].Chen W, Liu Y, Li L, Zeng X. Efficacy and safety of thrombopoietin receptor agonists in solid tumors with chemotherapy-induced thrombocytopenia: a meta-analysis. BMC Pharmacol Toxicol 2023;24(1):71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [25].Garabet L, Ghanima W, Monceyron Jonassen C, et al. Effect of thrombopoietin receptor agonists on markers of coagulation and P-selectin in patients with immune thrombocytopenia. Platelets 2019;30(2):206–212. [DOI] [PubMed] [Google Scholar]
- [26].Winer ES, Safran H, Karaszewska B, et al. Eltrombopag for thrombocytopenia in patients with advanced solid tumors receiving gemcitabine-based chemotherapy: a randomized, placebo-controlled phase 2 study. Int J Hematol 2017;106(6):765–776. [DOI] [PubMed] [Google Scholar]
- [27].Zhu QH, Yang SM, Zeng WB, et al. A real-world observation of eltrombopag and recombinant human thrombopoietin (rhTPO) in lymphoma patients with chemotherapy induced thrombocytopenia. Front Oncol 2021;11:701539. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [28].Shoukier M, Borthakur G, Jabbour E, et al. The effect of eltrombopag in managing thrombocytopenia associated with tyrosine kinase therapy in patients with chronic myeloid leukemia and myelofibrosis. Haematologica 2021;106(11):2853–2858. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [29].Ito M, Kanda S, Yoshida T, et al. Eltrombopag olamine for refractory immune-related thrombocytopenia induced by pembrolizumab in a non-small cell lung cancer patient. Lung Cancer 2020;146:362–365. [DOI] [PubMed] [Google Scholar]
- [30].Harada S, Imakura T, Sato S, Nokihara H, Nishioka Y. A case of successful treatment with eltrombopag for severe immune-related thrombocytopenia induced by atezolizumab: case report. J Med Invest 2023;70(3.4):516–520. [DOI] [PubMed] [Google Scholar]