Abstract
Background
Chemotherapy-induced thrombocytopenia (CIT) is a common hematological complication in patients with cancer. Hetrombopag is a novel thrombopoietin receptor agonist that has shown an additive effect in stimulating platelet production when combined with recombinant human thrombopoietin (rhTPO).
Objectives
This multicenter retrospective cohort study aimed to evaluate the efficacy and safety of hetrombopag plus rhTPO compared with rhTPO alone for CIT.
Methods
A total of 294 patients with solid tumors and CIT (platelet count, <50 × 109/L) who received either rhTPO plus hetrombopag (146 patients) or rhTPO alone (148 patients) at 3 centers from January to December 2022 were included in the study. The primary outcome was a platelet count at least 50 × 109/L higher than the baseline value within 14 days. Chemotherapy dose reductions/delays, bleeding, and adverse events were reported.
Results
One hundred twenty patients (82.2%) in the rhTPO-hetrombopag group vs 100 patients (67.6%) in the rhTPO group achieved the primary outcome (P = .005). This significant difference persisted in adjusted analysis (odds ratio, 2.01; 95% CI, 1.12-3.60). A total of 115 patients (78.8%) in the rhTPO-hetrombopag group and 101 patients (68.2%) in the rhTPO group avoided chemotherapy dose reductions/delays (P = .041). There was no significant difference in bleeding rates, and adverse events were mild and similar between the 2 groups. No deaths occurred.
Conclusion
Compared to rhTPO alone, our findings suggest that the combination of hetrombopag and rhTPO is safe and more effective in patients with CIT.
Keywords: cancer, chemotherapy, hetrombopag, thrombocytopenia, thrombopoietin
Graphical abstract
Essentials
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Chemotherapy-induced thrombocytopenia (CIT) is common in patients with cancer.
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Recombinant human thrombopoietin (rhTPO) with or without hetrombopag was retrospectively compared in CIT.
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Platelet count improvement was greater in patients receiving hetrombopag and rhTPO.
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Hetrombopag plus rhTPO is safe and more effective for CIT than rhTPO alone.
1. Introduction
Chemotherapy-induced thrombocytopenia (CIT) is one of the most common hematological complications among patients with cancer treated with cytotoxic chemotherapy [1,2]. CIT can result in dose reduction, interruption or delay of cancer treatment, and increased risk of bleeding, ultimately affecting overall survival and increasing medical expenses [3,4]. Shaw et al. [5] reported that the incidence rate of CIT in patients with solid tumors is 13%. Platelet transfusion only transiently raises platelet counts and may also cause some side effects, such as infection, refractoriness, and alloimmunization [6,7].
Thrombopoietin (TPO) is a hematopoietic cytokine that binds to the extracellular domain of TPO receptors, specifically c-Mpl, and stimulates multiple signaling pathways, including STAT, PI3K, and ERK, to promote megakaryocyte duplication and differentiation into platelets [[8], [9], [10], [11]]. Recombinant human thrombopoietin (rhTPO) is expressed in Chinese hamster ovary cells and purified to a full-length glycosylated TPO with an identical amino acid sequence to endogenous TPO [12]. Previous studies have shown that rhTPO improved the lowest platelet counts, shortened the duration of thrombocytopenia, and reduced the need for platelet transfusion in patients receiving chemotherapy [13,14]. Hence, rhTPO is widely used for the treatment of CIT in China [15]. Nevertheless, some patients do not respond well to rhTPO. In recent years, thrombopoietin receptor agonists (TPO-RAs) have been developed, have rapidly entered clinical trials, and have shown promising therapeutic effects in CIT [16]. The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for Hematopoietic Growth Factors V.2.2023 recommend that patients participate in clinical trials of TPO-RAs [17].
Hetrombopag (Hengqu, Jiangsu Hengrui Medicine Co, Ltd) is an oral, small molecule, synthetic nonpeptide TPO-RA that binds to the transmembrane domain of TPO receptors and complements the role of natural TPO [18]. In June 2021, hetrombopag was first approved in China for the treatment of chronic primary immune thrombocytopenia and severe aplastic anemia [19]. However, hetrombopag has not yet been approved for the treatment of CIT. A preclinical study demonstrated that the combination of hetrombopag and rhTPO showed additive effects in stimulating TPO receptor–dependent signaling, promoting cell viability, and preventing apoptosis in human TPO receptor–transfected murine 32D cells [20]. Therefore, we hypothesized that the combination of rhTPO and hetrombopag treatment might be more effective for CIT management than rhTPO alone.
In clinical practice, hetrombopag has been applied to patients with CIT and has shown a certain efficacy [21,22], but few studies have been published on its application for this condition to date. Hence, we conducted this observational study to evaluate the efficacy and safety of the hetrombopag-rhTPO combination for managing CIT in patients with solid tumors.
2. Methods
This retrospective study was approved by the Ethics Committee of Tongji Hospital affiliated with Huazhong University of Science and Technology, and the requirement for informed consent was waived. Patients aged ≥18 years with solid tumors and experiencing thrombocytopenia (defined as the occurrence of platelet counts of <50 × 109/L in the chemotherapy cycle) who received either rhTPO plus hetrombopag or rhTPO alone at Tongji Hospital, Yichang Central People’s Hospital, and Xiangyang Central Hospital from January to December 2022 were included in this study. A platelet count of 50 × 109/L was chosen as the critical value because a platelet count of 50,000/μL was the threshold for increased bleeding risk and major invasive surgery recommended by the panel [23,24]. Patients with other causes of thrombocytopenia, such as nonanticancer drugs, hepatitis C, and megaspleen, were ineligible. Other exclusion criteria included lack of follow-up documentation, sequential hetrombopag treatment following rhTPO, a history of hematologic diseases other than CIT, significant cardiovascular disease, treatment with other TPO-RAs or recombinant human interleukin 11 (rhIL-11), transaminase or total bilirubin >3 upper limit of normal in nonliver cancer, and pregnancy.
Hetrombopag (Hengqu) or rhTPO (TPIAO, Shenyang 3SBIO, Inc) was initiated when the platelet count fell below 50 × 109/L after chemotherapy and was stopped when the platelet count was >100 × 109/L or 50 × 109/L more than the baseline value. The baseline platelet count was recorded the day before or on the day of thrombopoietic support. The first day of administration was designated as day 1 of the observation. rhTPO was administered subcutaneously at 15,000 U daily, whereas hetrombopag was administered orally (7.5 mg, daily).
Demographic information and clinical data were obtained from the medical records. We recorded the dates of administration and platelet counts of the patients after drug administration to measure the effect of platelet increase. The primary outcome was a platelet count at least 50 × 109/L higher than the baseline value within 14 days of treatment initiation. Secondary outcomes were as follows: (1) complete response rate (platelet count of ≥100 × 109/L and absence of bleeding), response rate (platelet counts of ≥30 × 109/L, at least 2-fold increase in the baseline platelet count, and absence of bleeding), and no response rate (platelet count of <30 × 109/L or less than 2-fold increase in the baseline platelet count or bleeding); (2) the proportion of patients whose platelet counts reached 50, 75, and 100 × 109/L; (3) the lowest and highest platelet counts after treatment; (4) the incidence of chemotherapy dose reduction or delay due to any reason, including thrombocytopenia; and (5) bleeding and adverse events (AEs). Bleeding grade was assessed using the World Health Organization bleeding classification standard [25]. AEs and grades were determined according to the Common Terminology Criteria for Adverse Events version 5.0.
Continuous variables were expressed as mean ± SD or median (range). Categorical variables were summarized as numbers and frequencies (percentages). Student’s t-test or Wilcoxon Mann–Whitney U-test was used to compare continuous outcomes between the 2 treatments. The chi-squared test and Fisher’s exact test were used to compare categorical variables. We made adjusted comparisons of the likelihood of achieving the primary outcome using a multivariable logistic model that included the following factors: thrombopoietic drugs, sex, age, cancer stage, primary tumor site, liver metastases, osseous metastases, radiotherapy, targeted therapy, immunotherapy, and platelet counts before chemotherapy. We performed a subgroup analysis to establish the consistency of the treatment effect according to baseline clinical and demographic characteristics. A P value of <.05 was considered statistically significant. Statistical analyses were performed using SPSS (version 21.0; SPSS Inc).
3. Results
3.1. Patient characteristics
Based on hospital records, 374 patients met the inclusion criteria. A total of 80 patients were excluded for the following reasons: 37 patients with the use of other TPO-RAs or rhIL-11, 34 patients with no follow-up, 7 patients receiving sequential therapy, and 2 patients with significant cardiovascular diseases. After applying exclusion criteria, 294 patients qualified for the study (146 on rhTPO plus hetrombopag and 148 on rhTPO). The median age was 58 years (range, 18-82 years), and 137 patients (46.6%) were female. Lung, gynecologic, and colorectal cancers were the most common tumors, accounting for more than half of all cases. Demographic and clinical baseline characteristics were similar between the groups (Table 1).
Table 1.
Demographic and baseline characteristics.
| Characteristic | rhTPO plus hetrombopag (n = 146) | rhTPO (n = 148) | P value |
|---|---|---|---|
| Sex, n (%) | .821 | ||
| Male | 77 (52.7) | 80 (54.1) | |
| Female | 69 (47.3) | 68 (45.9) | |
| Age (y), median (range) | 59 (18-80) | 58 (18-82) | .168 |
| Age group (y), n (%) | .080 | ||
| <60 | 77 (52.7) | 93 (62.8) | |
| ≥60 | 69 (47.3) | 55 (37.2) | |
| Ethnicity | Han Chinese | Han Chinese | |
| BMI (kg/m2), mean ± SD | 22.04 ± 3.34 | 21.95 ± 3.31 | .808 |
| Tumor type, n (%) | .602 | ||
| Brain | 3 (2.1) | 5 (3.4) | |
| Breast | 13 (8.9) | 11 (7.4) | |
| Gastroesophageal | 18 (12.3) | 17 (11.5) | |
| Genitourinary | 2 (1.4) | 4 (2.7) | |
| Colorectal | 22 (15.1) | 15 (10.1) | |
| Gynecologic | 19(13.0) | 16 (10.8) | |
| Head and neck | 10 (6.8) | 18 (12.2) | |
| Hepatobiliary | 10 (6.8) | 16 (10.8) | |
| Lung | 37 (25.3) | 39 (26.4) | |
| Pancreatic | 5 (3.4) | 2 (1.4) | |
| Sarcoma | 7 (4.8) | 5 (3.4) | |
| Cancer stage, n (%) | .901 | ||
| I | 10 (6.8) | 10 (6.8) | |
| II | 15 (10.3) | 16 (10.8) | |
| III | 48 (32.9) | 45 (30.4) | |
| IV | 73 (50.0) | 77 (52.0) | |
| Liver metastases, n (%) | 43 (29.5) | 48 (32.4) | .580 |
| Osseous metastases, n (%) | 25 (17.1) | 31 (20.9) | .459 |
| Combined with radiation therapy, n (%) | 35 (24.0) | 50 (33.8) | .064 |
| Combined with targeted therapy, n (%) | 31 (21.2) | 30 (20.3) | .839 |
| Combined with immunotherapy, n (%) | 34 (23.3) | 33 (22.3) | .840 |
| Platelet count before chemotherapy (×109/L), mean ± SD | 154 ± 91 | 166 ± 89 | .239 |
| Baseline platelet count (×109/L), mean ± SD | 33 ± 16 | 34 ± 13 | .130 |
BMI, body mass index; rhTPO, recombinant human thrombopoietin.
3.2. Efficacy
A total of 220 patients achieved the primary outcome, including 120 patients (82.2%) in the rhTPO-hetrombopag group and 100 patients (67.6%) in the rhTPO group (P = .005; Table 2).
Table 2.
Incidence proportion of selected outcomes.
| Criteria | rhTPO plus hetrombopag | rhTPO | P value |
|---|---|---|---|
| Primary outcome | |||
| Platelet levels increased by 50 × 109/L from baseline value, n (%) | 120 (82.2) | 100 (67.6) | .005 |
| Secondary outcome | |||
| Platelet levels to recover to 50 × 109/L, n (%) | 132 (90.4) | 126 (85.1) | .168 |
| Platelet levels to recover to 75 × 109/L, n (%) | 124 (84.9) | 105 (70.9) | .004 |
| Platelet levels to recover to 100 × 109/L, n (%) | 101 (69.2) | 82 (55.4) | .015 |
rhTPO, recombinant human thrombopoietin.
The complete response, response, and no response rates were 65.1% (95/146), 15.8% (23/146), and 19.2% (28/146) in the rhTPO-hetrombopag group and 52.0% (77/148), 13.5% (20/148), and 34.5% (51/148) in the rhTPO group, respectively (P = .012). A total of 132 (90.4%), 124 (84.9%), and 101 (69.2%) patients in the rhTPO-hetrombopag group and 126 (85.1%), 105 (70.9%), and 82 (55.4%) patients in the rhTPO group achieved a platelet count of 50, 75, and 100 × 109/L, respectively (P = .168, P = .004, and P = .015, respectively).
Mean baseline platelet count (×109/L) was 33 ± 16 in the rhTPO-hetrombopag group and 34 ± 13 in the rhTPO group (P = .364). The lowest platelet count (×109/L) in the rhTPO-hetrombopag group was 30 ± 16 compared with 29 ± 14 in the rhTPO group (P = .428). The highest platelet level (×109/L) in the rhTPO-hetrombopag group was 152 ± 108, compared with 146 ± 131 in the rhTPO group (P = .669).
The results of multivariable analysis were presented in Table 3. We found that patients treated with rhTPO plus hetrombopag were significantly likely to achieve the primary outcome (odds ratio [OR], 2.01; 95% CI, 1.12-3.60). Patients who had osseous metastases (OR, 0.43; 95% CI, 0.21-0.85) and underwent radiotherapy (OR, 0.42; 95% CI, 0.22-0.79) were less likely to achieve the primary outcome. Other factors had no significant effect on the primary outcome. As shown in the Figure, a subgroup analysis of platelet count increase over baseline of 50 × 109/L was performed to compare treatment effects. A benefit in terms of platelet count improvement was consistently observed with rhTPO plus hetrombopag. For patients receiving combined chemoradiotherapy, 30 of 35 (85.7%) in the rhTPO-hetrombopag group and 24 of 50 (40.8%) in the rhTPO group achieved the primary outcome (OR, 6.50; 95% CI, 2.17-19.48).
Table 3.
Adjusted odds of achieving the primary outcome.
| Covariable | OR (95% CI) |
|---|---|
| Drug | |
| rhTPO (ref) | |
| rhTPO plus hetrombopag | 2.01 (1.12-3.60) |
| Sex | |
| Female (ref) | |
| Male | 1.45 (0.80-2.63) |
| Age | |
| <60 (ref) | |
| ≥60 | 1.52 (0.82-2.82) |
| Cancer stage | |
| I-II (ref) | |
| III-IV | 0.63 (0.26-1.52) |
| Tumor with primary site in liver/digestive tract/bone | |
| No (ref) | |
| Yes | 0.82 (0.60-1.65) |
| Liver metastases | |
| No (ref) | |
| Yes | 0.54 (0.28-1.03) |
| Osseous metastases | |
| No (ref) | |
| Yes | 0.43 (0.21-0.85) |
| Combined with radiotherapy | |
| No (ref) | |
| Yes | 0.42 (0.22-0.79) |
| Combined with targeted therapy | |
| No (ref) | |
| Yes | 0.60 (0.30-1.21) |
| Combined with immunotherapy | |
| No (ref) | |
| Yes | 0.59 (0.30-1.17) |
| Platelet count before chemotherapy | |
| ≥100 × 109/L (ref) | |
| <100 × 109/L | 0.79 (0.39-1.60) |
OR, odds ratio; ref, reference; rhTPO, recombinant human thrombopoietin.
Figure.
Subgroup analyses for the primary outcome. BMI, body mass index; rhTPO, recombinant human thrombopoietin.
There were 115 patients (78.8%) in the rhTPO-hetrombopag group and 101 (68.2%) patients in the rhTPO group who avoided chemotherapy dose reductions/delays (P = .041).
3.3. Safety
A total of 31 patients experienced bleeding during the recording period, at an overall rate of 10.5%, including 13 in the rhTPO-hetrombopag group and 18 in the rhTPO group. Among them, 6 patients (2.0%) had bleeding due to tumor invasion. Twenty-five of the total number of patients who experienced bleeding had a platelet count of <50 × 109/L. No grade 4 bleeding events occurred during the study period. No statistically significant difference was found between the 2 groups (P = .574; Table 4). In this study, 39 patients (26.7%) in the rhTPO-hetrombopag group and 39 patients (26.4%) in the rhTPO group received platelet transfusion. No statistically significant differences were observed (P = .944; Table 4).
Table 4.
Bleeding, platelet transfusion, and adverse events.
| Event | rhTPO plus hetrombopag | rhTPO | P value |
|---|---|---|---|
| Any bleeding, n (%) | .574 | ||
| Grade 1a | 7 (4.8) | 13 (8.8) | |
| Grade 2 | 4 (2.7) | 3 (2.0) | |
| Grade 3 | 2 (1.4) | 2 (1.4) | |
| Platelet transfusion, n (%) | 39 (26.7) | 39 (26.4) | .944 |
| Elevated liver enzymes, n (%) | 9 (6.2) | 9 (6.1) | .904 |
| Hyperbilirubinemia, n (%) | 3 (2.1) | 2 (1.4) | .525 |
| Thromboembolic events, n (%) | 1 (0.7) | 1 (0.7) | >.999 |
| Fever, n (%) | 8 (5.5) | 8 (5.4) | .898 |
| Diarrhea, n (%) | 6 (4.1) | 8 (5.4) | .785 |
| Fatigue, n (%) | 11 (7.5) | 11 (7.4) | .912 |
| Dizzy, n (%) | 1 (0.7) | 5 (3.4) | .214 |
rhTPO, recombinant human thrombopoietin.
The bleeding grade was assessed using the World Health Organization bleeding classification standard.
A total of 83 cases involving 7 types of AEs were recorded in 62 patients, occurring in 29 (19.9%) patients in the rhTPO-hetrombopag group and in 33 (22.3%) patients in the rhTPO group. The AEs in the 2 groups were similar. One patient (0.7%) with metastatic pancreatic cancer in the rhTPO-hetrombopag group experienced an upper extremity deep vein thrombosis and had a platelet count of 113 × 109/L at the time. One patient (0.7%) in the rhTPO group, a 76-year-old male patient with squamous cell lung cancer who had been receiving paclitaxel/platinum chemotherapy, developed an upper extremity deep vein thrombosis. His platelet count was 282 × 109/L at the time. They received enoxaparin treatment without further thrombotic event. No pulmonary embolism was observed. The elevated transaminase and hyperbilirubinemia levels were corrected after a period of treatment, and the other AEs were relieved without intervention. All AEs were mild and, no deaths occurred.
4. Discussion
Thrombocytopenia is a prevalent problem among patients with cancer, and its treatment presents a continuing challenge. In China, rhTPO and rhIL-11 are the only drugs approved for use in CIT. rhIL-11 has an associated risk of edema and atrial fibrillation [26]. In contrast, rhTPO has not been reported to cause these side effects in postmarketing adverse reaction monitoring studies [15]. Hetrombopag exhibits high pharmacological potency and a durable platelet response, encouraging activity with multilineage hematologic responses, along with a reduced bleeding risk and long-term safety [20,[27], [28], [29], [30]]. However, there are only a few reports regarding its application in CIT. Therefore, we conducted a retrospective study to compare the efficacy and safety of rhTPO plus hetrombopag with those of rhTPO alone for the treatment of CIT in patients with solid tumors.
As shown in the Results section, patients treated with hetrombopag plus rhTPO exhibited greater platelet count improvement compared with those treated with rhTPO alone. A recent retrospective study evaluating rhTPO combined with hetrombopag in patients with thrombocytopenia undergoing cancer therapy (platelet count, <50 × 109/L) illustrated that 21 of 28 (75.0%) patients treated with rhTPO plus hetrombopag achieved an increase in platelet count of >50 × 109/L, or doubling from baseline or reaching >100 × 109/L without platelet transfusion within 7-day treatment [21]. In several prospective trials of romiplostim, another TPO-RA in adults with CIT (platelet count, <100 × 109/L), a primary endpoint of platelet count correction to ≥100 × 109/L within 3 weeks, was met in 44 (85%) patients [31], and a romiplostim response of median platelet counts of ≥75 × 109/L and ≥30 × 109/L above baseline was achieved in 71% of patients [32]. Additionally, an observational study of another TPO-RA, eltrombopag, for the treatment of CIT in patients (platelet count, <30 × 109/L) with lymphoma showed that the time to a platelet count recovery of 75 × 109/L was 7.43 ± 2.54 days [33].
Chemoradiotherapy is a crucial modality in cancer treatment. Irradiation damages stem cells and the microenvironment, and causes thrombocytopenia for a longer period of time than chemotherapy [7,34]. Our results suggest that combined radiotherapy play a negative role in the recovery of CIT. In the subgroup analysis, patients treated with combined radiotherapy in the rhTPO-hetrombopag group still showed greater platelet count improvement compared with that in those treated with rhTPO alone. This finding is encouraging for such patients. With the continuous optimization of the irradiation target area, irradiation intensity, and fractionated dose of radiotherapy, it has been possible to avoid the impact of radiotherapy on normal organs and tissues. But there are still reports of radiotherapy-induced thrombocytopenia [35]. Research investigating interventions for radiotherapy-induced thrombocytopenia remains limited. Therefore, further investigation is necessary to understand radiotherapy-related adverse hematological reactions.
Chemotherapy dose reduction and treatment delays are the current standards of care for the management of CIT. In this study, more patients in the rhTPO-hetrombopag group continued treatment without chemotherapy dose reduction/delay, which could potentially have a clinical benefit. Several other studies have reported that patients with CIT treated with romiplostim or eltrombopag had a lower dose reduction/delay [32,[36], [37], [38]]. However, a phase 3 study indicated no significant difference in chemotherapy dose reduction or treatment delay between patients treated with avatrombopag and placebo, likely because of the higher rate of spontaneous platelet count recovery in the placebo group [39].
A platelet count of 50 × 109/L is considered the threshold for major invasive surgery [23,24]. For patients with cancer undergoing chemotherapy, the probability of bleeding when the platelet count is below this value is 9.6%, and when platelet count falls below 20 × 109/L, the bleeding probability rises to 10.1% to 17.7% [40]. A large retrospective cohort consisting of 609 patients with cancer and CIT in 1262 chemotherapy cycles reported that the incidence of bleeding occurred in 9% of cycles [4]. In another earlier study, 75 (10.4%) patients with CIT experienced hemorrhage and the majority of bleeding events occurred in patients with platelet counts of <10000/μL [41]. Dutcher et al. [42] reported 44 episodes of clinically detectable serious bleeding among 301 patients with CIT, and 147 of the 301 patients received platelet transfusions. In our research, the bleeding rate of patients treated with rhTPO plus hetrombopag was 8.9% (13/146) and that of patients treated with rhTPO alone was 12.2% (18/148), and no statistically significant difference between the 2 groups was found. Combined therapy did not show a lower bleeding rate compared with that with rhTPO alone. We also observed that the platelet transfusion rate was much higher than the bleeding rate in both groups, indicating that platelet transfusion was utilized not only to treat bleeding but also to prevent it. In an international, randomized, placebo-controlled study on the treatment of CIT with avatrombopag, the rates of platelet transfusion were similar between the avatrombopag and placebo groups [39]. Past practice indicated that patients with platelet counts of <20 × 109/L required prophylactic platelet transfusion [43]. However, the American Society of Clinical Oncology updated the clinical practice guideline in 2018 to recommend that the threshold of prophylactic platelet transfusion in patients with hematological malignancies or solid tumors be lowered to 10 × 109/L [23].
Regarding safety, the types and incidences of AEs were similar between the 2 groups, all of which were mild, and no treatment-related deaths were observed. Similar to our results, previous studies on hetrombopag reported various degrees of AEs. Two phase 1 studies demonstrated that elevated platelet count accounted for the majority of AEs, which was in accordance with our results, and discovered a positive correlation between dose and incidence of the AE in healthy individuals receiving oral hetrombopag [20,29]. The most common AEs in other studies were upper respiratory tract infection [27,28] and skin and subcutaneous tissue disorders (28.1%) [44], with the majority of them being grade 1 or 2. To date, all studies of hetrombopag have demonstrated its safety in adults. Fever, dizziness, diarrhea, and elevated liver enzyme levels have also been observed in patients treated with eltrombopag and romiplostim [[45], [46], [47], [48], [49]]. Thromboembolic events were also assessed, with venous thromboembolism (VTE) being a common occurrence in patients with cancer, particularly those undergoing chemotherapy. A previous study reported that 12.6% of patients in a solid tumor cohort experienced a VTE within 12 months [50]. In this study, the incidence rate of VTE was found to be 17.9 per 100 person-years in the rhTPO-hetrombopag group and 17.6 per 100 person-years in the rhTPO group, indicating similar rates between the 2 groups. All patients who developed VTE had high-risk sites of cancer for VTE development [51]. However, the short follow-up time may have affected the accuracy of the results. None of the VTEs were considered to be related to thrombopoietic agents. In general, hetrombopag and rhTPO were well tolerated. In addition, administration of hetrombopag avoided injection pain and ecchymosis of rhTPO and reduced the need for close contact with individuals in the hospital during the coronavirus outbreak.
Our study has several limitations that should be considered. First, this is a retrospective study on therapeutic effects, and the data collected are based on correct medical records. There may have been bias and other unavoidable confounding factors. We tried to control for some confounding variables by performing a multivariable analysis. Additionally, the exclusion of discharged patients due to unavailable data during treatment and spontaneous platelet count recovery in both groups of patients might have impacted the observed outcomes. Second, the sample size may have limited our ability to detect meaningful differences. Generalizability of the study results to other populations should be made with caution. Third, our follow-up time was not long enough; events that might occur after a long period of time will be missed. Furthermore, because of the limited number of patients with CIT treated with hetrombopag alone, we selected patients who received the combination of hetrombopag and rhTPO. Therefore, prospective studies are required to explore the efficacy and safety of hetrombopag alone in patients with CIT.
In conclusion, our study suggests that the combination of hetrombopag and rhTPO may be a safe and more effective option in patients with CIT.
Acknowledgments
The authors would like to thank all study investigators and coordinators.
Funding
This study was supported by the Medical Research Project of the Medical Science Research Fund of the Beijing Medical and Health Public Welfare Foundation (YWJKJJHKYJJ-F1802B).
Ethics statement
This retrospective study was approved by the Ethics Committee of Tongji Hospital affiliated with Huazhong University of Science and Technology, and the requirement for informed consent was waived.
Author contributions
H.X. and X.X. designed the study. H.X., Q.H., and Y.W. provided the study materials and patients. H.X., X.X., H.Z., H.Z., W.D., R.L., Q.H., and Y.W. collected and assembled the data. H.X. and X.X. analyzed the data. X.X. wrote the paper.
Relationship Disclosure
There are no competing interests to disclose.
Data availability
We agree to share publication-related data through communication via email with the corresponding author.
Footnotes
Handling Editor: Dr Bethany Samuelson Bannow
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