Chemotherapy-induced Thrombocytopenia Research Articles

Risk Factors of Chemotherapy-Induced Thrombocytopenia After Oxaliplatin-Containing Chemotherapy for Gastrointestinal Malignancies.

Thrombocytopenia is among the most common chemotherapy-related hematologic toxicities. We aim to determine the predictors of oxaliplatin chemotherapy-induced thrombocytopenia in patients with gastrointestinal tumors to guide the clinic. Clinical data of 750 patients with a malignant gastrointestinal tumor were included as the primary cohort. Basic clinical data, serological indices, and anthropometric indices of these patients were collected. According to the presence or absence of CIT, univariate analysis was performed to identify significant factors for multivariate analysis. In R language software, nomogram was constructed based on the results of multi-factor analysis, and the calibration curve and ROC curve were drawn. Univariate analysis identified 17 factors as closely related to CIT occurrence, namely age, lymph node metastasis (N) stage, metastasis (M) stage, lung metastasis, other site metastasis, chemotherapy regimen, course of treatment, total dose of oxaliplatin, AST, albumin, neutrophils, monocytes, baseline platelets, transferrin, natural killer (NK) cell, phase angle, and SMI (P < 0.10). The binary logistic multivariate regression analysis revealed five independent risk factors for developing CIT (P < 0.05), including the M stage, total dose of oxaliplatin, albumin, baseline thrombocyte count, and NK cell. Based on the results of multivariate logistic regression analysis, R software was used to establish a nomogram model. The calibration curve shows that the combined predictor has good consistency. The area under the ROC curve was 0.877 and the best cut-off value was 0.3579613 (sensitivity, 78.9%; specificity, 81.8%), which showed the better prediction efficiency. The total dose of oxaliplatin, M stage, albumin, baseline platelet count, and NK cell was independent risk factors for CIT. The sequentially constructed histogram model had a good predictive effect on the risk of thrombocytopenia caused by oxaliplatin chemotherapy in patients with gastrointestinal malignancies.

Prediction Model for Severe Thrombocytopenia Induced by Gemcitabine Plus Cisplatin Combination Therapy in Patients with Urothelial Cancer.

Chemotherapy-induced thrombocytopenia is often a use-limiting adverse reaction to gemcitabine and cisplatin (GC) combination chemotherapy, reducing therapeutic intensity, and, in some cases, requiring platelet transfusion. A retrospective cohort study was conducted on patients with urothelial cancer at the initiation of GC combination therapy and the objective was to develop a prediction model for the incidence of severe thrombocytopenia using machine learning. We performed receiver operating characteristic analysis to determine the cut-off values of the associated factors. Multivariate analyses were conducted to identify risk factors associated with the occurrence of severe thrombocytopenia. The prediction model was constructed from an ensemble model and gradient-boosted decision trees to estimate the risk of an outcome using the risk factors associated with the occurrence of severe thrombocytopenia. Of 186 patients included in this study, 46 (25%) experienced severe thrombocytopenia induced by GC therapy. Multivariate analyses revealed that platelet count ≤ 21.4 (×104/µL) [odds ratio 7.19, p<0.01], hemoglobin ≤ 12.1 (g/dL) [odds ratio 2.41, p=0.03], lymphocyte count ≤ 1.458 (×103/µL) [odds ratio 2.47, p=0.02], and dose of gemcitabine ≥ 775.245 (mg/m2) [odds ratio 4.00, p<0.01] were risk factors of severe thrombocytopenia. The performance of the prediction model using these associated factors was high (area under the curve 0.76, accuracy 0.82, precision 0.68, recall 0.50, and F-measure 0.58). Platelet count, hemoglobin level, lymphocyte count, and gemcitabine dose contributed to the development of a novel prediction model to identify the incidence of GC-induced severe thrombocytopenia.

Use of romiplostim for antineoplastic therapy-induced thrombocytopenia in gynecologic and breast cancers

ObjectiveRomiplostim is used to treat chemotherapy-induced thrombocytopenia in a variety of tumor types; however, few studies have examined its use in breast and gynecologic cancers. We evaluated platelet response and durability of response to romiplostim in patients with gynecologic or breast cancer complicated by chemotherapy-induced thrombocytopenia. MethodsWe retrospectively identified 33 patients with gynecologic or breast cancer who received romiplostim between 07/1/2021–07/31/2022 at an academic cancer center. ResultsThirty-three patients met inclusion criteria; 26 (79 %) had breast cancer, 4 (12 %) had ovarian cancer, and 3 (9 %) had endometrial cancer. Twenty patients (61 %) experienced treatment delays and 12 (36 %) required dose reductions prior to starting romiplostim for chemotherapy-induced thrombocytopenia, with some patients experiencing both. Eleven patients (33 %) did not undergo a dose reduction or delay prior to initiation of romiplostim. Median platelet count prior to romiplostim therapy was 53 k/mcL (range, 40.5–78.8). Median platelet count within 3 weeks following initiation of romiplostim was 147 k/mcL (range, 31–562). Twenty-one patients (64 %) achieved platelet correction within 3 weeks, of whom 10 (48 %) resumed anticancer therapy and maintained platelet levels above 100 k/mcL at 8 weeks. Twelve patients did not achieve platelet correction within 3 weeks of romiplostim initiation; 4 (33 %) required a treatment change secondary to persistent thrombocytopenia, 3 (25 %) required a treatment dose reduction, 3 (25 %) were deemed too ill to continue therapy, and 2 (17 %) required a treatment delay. ConclusionsRomiplostim facilitated the resumption of anticancer therapy in 64 % of patients with gynecologic or breast cancer complicated by chemotherapy-induced thrombocytopenia.

Cancer-associated thrombosis and bleeding.

Development of thrombosis is closely associated with poor prognosis in cancer patients. Cancer patients often fulfill Virchow's triad of hyper-coagulable state, vascular endothelial injury, and venous stasis. Cancer cells aberrantly express a variety of procoagulant factors, including tissue factor and podoplanin. Chemotherapeutic agents and radiation cause vascular endothelial injury, and reduced daily activity and bed rest for chemotherapy lead to venous stasis. Due to these factors, cancer patients are at high risk of developing thrombosis. Cancer patients are also at high risk of bleeding when they have disseminated intravascular coagulation and/or chemotherapy-induced thrombocytopenia as complications. International societies, such as the American Society of Clinical Oncology and the International Initiative on Thrombosis and Cancer (ITAC), have published clinical guidelines to help physicians better manage cancer-associated thrombosis (CAT). These guidelines recommend use of low molecular weight heparin or direct oral anticoagulants for the prevention of CAT, but unfortunately use of these drugs is not approved in Japan. This gap between Japan and other countries needs to be closed.

Anticoagulation in cancer patients with atrial fibrillation and grade 3–4 thrombocytopenia

IntroductionAtrial fibrillation or flutter (AF) is prevalent in cancer patients. Many of these patients have an indication for anticoagulation (AC) but are also at risk for developing chemotherapy-induced thrombocytopenia. There are scarce data regarding management of AC and risk of bleeding and thrombosis in cancer patients with AF and thrombocytopenia. AimTo assess anticoagulation management and incidence of bleeding and arterial thromboembolism (ATE) in cancer patients with AF and grade 3–4 thrombocytopenia (platelets <50 × 109/L). MethodsA retrospective cohort study included adults with active cancer, grade 3–4 thrombocytopenia and AF with CHA2DS2-VASc score ≥ 1. Patients were stratified according to AC discontinuation (No-AC) or continuation (Continue-AC) when platelets dropped below 50 × 109/L and followed for 30 days. The study outcomes were ATE (ischemic stroke, transient ischemic attack or systemic emboli) and major bleeding. Cox proportional hazards model was used to calculate hazard ratios (HR) with death as a competing risk (Fine and Gray model). ResultsThe cohort included 131 patients; 90 in the No-AC group and 41 in the Continue-AC group. Patient characteristics were balanced between the groups. The 30-day cumulative incidence of ATE was 2 % [95 % CI 0.4 %–7 %] in the No-AC group and 2 % [0.2 %–11 %] in the Continue-AC group (HR 0.92 [95 % CI 0.09–9.88]). The 30-day cumulative incidence of major bleeding was 7.8 % [95 % CI 3.40 %–14.52 %] and 2.44 % [95 % CI 0.18 %–11.22 %] in the No-AC and Continue-AC groups, respectively (HR 3.29 [95 % CI 0.42–26.04]). ConclusionsThe high rate of bleeding and low rate of ATE in thrombocytopenic cancer patients with AF suggests that holding AC during time-limited periods may be a reasonable approach.

Effects of quercetin and extracts from Phyllanthus emblica, Morus alba, and Ginkgo biloba on platelet recovery in a rat model of chemotherapy-induced thrombocytopenia

BackgroundChemotherapy-induced thrombocytopenia (CIT) is a major reason for chemotherapy delays, dose reduction, or even treatment discontinuation, which may impact oncologic outcomes. We investigated the effects of quercetin and extracts of Phyllanthus emblica fruit (PEE), Morus alba leaf (MAE), and Ginkgo biloba leaf (GBE) on platelet recovery in a rat model of chemotherapy-induced thrombocytopenia. MethodsThe total phenolic content (TPC), total flavonoid content (TFC), quercetin content, and antioxidant activities of all the extracts were determined. Sixty male Sprague Dawley rats were categorized into healthy controls and CIT groups. The CIT groups was administered a cyclophosphamide solution, while the control group received a saline solution. Each group was then subdivided into five subgroups of six animals which were administered with PEE, MAE, GBE, quercetin, or a vehicle for 15 days. ResultsThe highest quercetin content was found in PEE, followed by MAE and GBE, which correlated with their antioxidant properties. Administration of these extracts and quercetin did not significantly change the platelet counts in healthy rats. Thrombocytopenic rats treated with PEE, MAE, and GBE also were not associated with significant changes in platelet counts. However, more rapid platelet count recovery was observed in all groups receiving extracts. On day 11, platelet counts in the PEE, MAE, and GBE groups returned to near baseline levels with a mean of 4.29 %, −40.77 %, and −14.24 %, respectively, compared to −71 % in the CIT group. In thrombocytopenic rats treated with quercetin, there was a significant increase in platelet counts on days 9 and 11, with a mean decrease of 5.41 % from baseline on day 11. ConclusionQuercetin improved platelet recovery in the animal model of CIT. This finding merits for further investigation to better elucidate the health benefits of quercetin and quercetin-rich plants and potential pharmacokinetics underpinning their activity in thrombocytopenia.

Role of thrombopoietin receptor agonists in chemotherapy-induced thrombocytopenia: A meta-analysis.

Chemotherapy-induced thrombocytopenia (CIT) is a significant challenge in cancer treatment, often leading to dose reductions and reduced number of cycles. The limited effectiveness of platelet transfusions in managing CIT highlights the need for alternative treatments. Thrombopoietin receptor agonists (TPO-RA), including romiplostim, eltrombopag and avatrombopag, have shown potential in increasing platelet counts in CIT patients, necessitating a comprehensive analysis of their efficacy. This meta-analysis followed the Preferred Reporting Items for Systemic Reviews and Meta-analysis guidelines, searching Ovid databases up to 5 October 2023. The primary metric of interest was platelet count changes post-TPO-RA administration in CIT patients. From the initial 867 studies obtained, 7 studies were selected based on the inclusion criteria. The analysis included 348 patients. A significant association was found between TPO-RA administration and platelet count increase, with a combined-effect increase of 69.52 ± 2.24 × 109/l. Subgroup analysis based on Romiplostim use suggested an increase of approximately 70.11 ± 39.07 × 109/l, while non-Romiplostim TPO-RAs showcased an increase of about 68.09 ± 82.58 × 109/l. The meta-analysis demonstrates the effectiveness of TPO-RAs in managing CIT. Further research comparing platelet increases across standardised TPO-RA regimens is recommended to refine treatment strategies. This analysis provides valuable insights for clinicians in tailoring CIT treatment using TPO-RAs.

Efficacy and Safety of Avatrombopag in the Treatment of Chemotherapy-Induced Thrombocytopenia in Children with Acute Lymphoblastic Leukemia: A Retrospective Study

Introduction: Chemotherapy-induced thrombocytopenia (CIT) is one of the most common complications during cancer treatment, increasing the risk of bleeding, medical costs, and potentially affecting treatment outcomes by necessitating chemotherapy dose reductions or delays. Avatrombopag, a thrombopoietin receptor agonist, has been approved as the first-line drug for the treatment of thrombocytopenia in chronic liver diseases. Its efficacy and safety was demonstrated in disorders like aplastic anemia and primary immune thrombocytopenia. However, the research regarding its use in children with CIT is lack. Objective: This retrospective study aimed to analyze the efficacy and safety of avatrombopag in the treatment of chemotherapy-induced thrombocytopenia in children with acute lymphoblastic leukemia, providing a potential new therapeutic option for managing CIT in pediatric cancer patients. Methods: The data of experimental group were collected from 30 pediatric patients with acute lymphoblastic leukemia and CIT who received avatrombopag treatment in the pediatric ward of Southern Hospital from August 2022 to July 2023. Additional data from 250 pediatric patients with acute lymphoblastic leukemia and CIT who did not receive avatrombopag treatment at Southern Hospital from January 2020 to July 2023 were collected as the control group. A propensity score matching method was employed to analyze the two patient groups, resulting in a successful matching of 30 pairs (CAT 21 pairs, CAT+9 pairs). The collected clinical data included age, gender, height, weight, risk stratification, infection status, platelet count changes during each chemotherapy cycle, platelet transfusion frequency, clinical manifestations of bleeding, avatrombopag usage, and complications. All patients were treated with the 2020-CCCG-ALL chemotherapy regimen,diagnosed with CIT,under 18 years of age, and excluded if they had concomitant hematological disorders, chronic liver disease, cardiovascular diseases, severe arterial or venous thrombosis, or splenomegaly. The initial avatrombopag dose was 10mg daily for patients weighing less than 30kg and 20mg daily for patients weighing 30kg or more. Avatrombopag was stopped when PLT≥100×10 9/L or an increase in PLT by ≥50×10 9/L compared to pre-treatment levels. Results: Comparison between the experimental and control groups revealed that the experimental group had a shorter duration of grade 3 or higher thrombocytopenia (3.36±1.77 days vs. 4.7±2.46 days, P=0.019) and a shorter time to platelet recovery (7.9±2.63 days vs. 9.76±2.77 days, P=0.01). Subgroup analysis within the CAT and CAT+ chemotherapy phases indicated that significant platelet value differences (P&amp;lt;0.05) were observed between the two groups at the start of platelet decline (day 10±2) [PLT: (268.13±216.52) ×10 9/L vs. (152.13±89.58) ×10 9/L] and during platelet nadir (day 14±2) [PLT: (435.97±285.83) ×10 9/L vs. (285.07±148.67) ×10 9/L]. Additionally, a statistically significant difference (P&amp;lt;0.05) in PLT change from baseline to day 5 and day 7 was observed in the experimental group [46.5 (20.5, 93) ×10 9/L and 67 (15.5, 180) ×10 9/L, respectively]. During the chemotherapy cycles, only 4 patients (8.3%) experienced bleeding events, and after avatrombopag treatment, 11 patients (22.9%) did not require platelet transfusions. Four adverse events of secondary platelet increase were recorded, and no other adverse events were reported. Conclusion: Avatrombopag, as an alternative treatment for chemotherapy-induced thrombocytopenia in children with acute lymphoblastic leukemia, demonstrated the potential to promote platelet recovery and exhibited good safety. keywords:avatrombopag,Chemotherapy-induced thrombocytopenia,acute lymphoblastic leukemia

Efficacy and Safety of Avatrombopag in the Treatment of Chemotherapy-Induced Thrombocytopenia Refractory to Rhtpo in Patients with Lymphoma

Background: Chemotherapy-induced thrombocytopenia (CIT) is a common cause of chemotherapy dose reductions and treatment delays. With applications of recombinant human interleukin 11 (rhIL-11) and recombinant human thrombopoietin (rhTPO), outcomes of patients with CIT have improved significantly. however，some patients with severe thrombocytopenia still have poor responses to the above therapies. Avatrombopag is an orally administered thrombopoietin receptor agonist and can stimulate thrombopoiesis in haematopoietic stem cells. Avatrombopag has been approved in the USA, Europe, and China for thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a surgery. It also has been approved for patients with chronic immune thrombocytopenia who are unresponsive to previous treatments in the USA and Europe. The aim of this study is to evaluate the efficacy and safety of avatrombopag in the treatment of refractory CIT. Methods: The clinical data of 23 lymphoma patients with grade 3/4 CIT unresponsive to rhTPO treatment for 7-10 days were collected from April 2022 to May 2023. All patients received avatrombopag orally at a dose of 40 to 60 mg / day combined with subcutaneous injection of rhTPO (300 U/kg/day). Response (R) was defined as a platelet count≥ 50 × /L, or doubling of the baseline platelet count, and absence of bleeding. Platelet transfusion was allowed when the platelet count was less than 10×109/L or with bleeding events. When the platelet count recovered to ≥100 ×10 9/L or increased 50 ×10 9/L from baseline, treatments of avatrombopag and rhTPO were stopped. Results: The median age of the 23 patients with refractory CIT was 57 (range 17‒83) years. The pathological subtypes were diffuse large B cell lymphoma (DLBCL) (n=10), Burkitt lymphoma (n=4), angioimmunoblastic T-cell lymphoma (AITL) (n=3), follicular lymphoma (FL) (n=2), extranodal NK/T cell lymphoma (ENKTL) (n=1), anaplastic large cell lymphoma (ALCL) (n=1), B-lymphoblastic lymphoma (n=1), and mantle cell lymphoma (MCL) (n=1). The treatment consisted of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) (n=11), Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone), high-dose methotrexate with cytarabine (n=6), liposomal mitoxantrone-containing regimen (n=4), bendamustine-containing regimen (n=1), and peg-asparaginase-based regimens (n=1). At baseline, 19 patients experienced grade 3 and 4 patients experienced grade 4 thrombocytopenia after chemotherapy. The median lowest platelet level was 12×10 9/L (range 2‒44×10 9/L). Two patients developed grade 1 bleeding events and one patient occurred grade 2 bleeding events. Nineteen patients received platelet transfusion. After receiving the combination therapy of avatrombopag, 73.9% (17/23)of patients achieved the primary end point of corrected platelet counts (≥50×10 9/L )and were free from platelet transfusion. The median time to response was 11 (range 5‒25) days. No treatment-related adverse events such as elevated aminotransferases, thrombosis, fatigue, fever and dizziness were noticed during administration. Two patients received avatrombopag as secondary prophylactic treatment, and there were no grade 4 thrombocytopenia or bleeding events during subsequent cycles of chemotherapy. Conclusion: Avatrombopag is effective and safe in the management of CIT for lymphoma and it can be used as an alternative / combination treatment for the patients who refractory to rhTPO. The further clinical research is still needed to confirm this conclusion.

Impact of Romiplostim on Overall Survival in Chemotherapy Induced Thrombocytopenia

BACKGROUND Romiplostim, a thrombopoietin receptor agonist, has been shown in a phase 2 trial to increase platelet count and facilitate chemotherapy administration in the setting of chemotherapy induced thrombocytopenia (CIT). The off-label use of romiplostim for this indication is common and is now a Category 2B recommendation by the National Comprehensive Cancer Network. Whether the administration of romiplostim improves clinical outcomes is not established. There are theoretical deleterious effects of platelet stimulation in cancer including the potential release of tumor stimulatory factors and blunting immune response to tumor cells. The goal of this retrospective study was to assess overall survival in patients with cancer treated with romiplostim compared to a cohort who received chemotherapy and granulocyte-colony stimulating factor (GCSF). The rationale for comparison of GCSF-treated arm was to address potential confounders related to chemotherapy dose reductions, delays, and abbreviated treatment courses due to cytopenias. METHODS To minimize cohort differences, we conducted an exact matched case-control analysis of patients with solid tumor malignancies receiving romiplostim with up to four patients receiving GCSF (without romiplostim). Patients were exact-matched based on a) primary cancer site, b) presence or absence of metastatic disease at the time of drug exposure, c) age (within 5 years), d) time from cancer diagnosis to treatment with romiplostim or G-CSF, 5) number of prior lines of antineoplastic therapy, and 6) comorbidities using the Charleston Comorbidity Illness index (&amp;lt;=6,7-10,&amp;gt;10). Overall survival (OS) was calculated from date of first dose of GCSF or romiplostim administration until death or last contact. Patient characteristics were summarized by frequency (percentage) and medians for categorical and continuous characteristics. OS was evaluated by Kaplan-Meier method and the difference between two treatment groups was determined by log-rank test. All statistical analyses were performed using R. RESULTS A total of 130 patients with solid tumor malignancy were identified as receiving romiplostim for CIT. Following strict exact-matching criteria, the analysis cohorts consisted of 58 patients in the romiplostim cohort and 138 patients in the GCSF cohort. The most common malignancies were Colorectal (18%), Non-Small Cell Lung Cancer (15%), Pancreas (13%). There was a median of 13 months between cancer diagnosis to romiplostim or and 16 months to GCSF and the mean number of prior lines of therapy was 2 in romiplostim and 1.8 in GCSF cohorts. The median comorbidity indices were similar in both groups (9 vs 9) and most patients had metastatic disease at the time of drug exposure (83%). The median overall survival in G-CSF treated patients was 18 months compared with romiplostim 10 months (Log rank P=0.014), Figure 1. In the stratified analysis by number of prior lines (1,2,&amp;gt;2), association with romiplostim remained statistically significant (Log rank P=0.012). Further restricting the analysis to patients who received romiplostim or GCSF during first or second lines of therapy, median overall survival in the romiplostim cohort (N=40) was 12 compared 21 months in the GCSF (N=109) cohort (log rank P=0.057), Figure 2. CONCLUSION In this retrospective exact-matched cohort analysis of patients treated with romiplostim for CIT, survival was inferior compared to patients receiving G-CSF alone. We acknowledge the limitations of single-center retrospective cohort analysis, but these findings highlight the urgent need to establish clinical benefit of thrombopoietin receptor agonists in the management of CIT.

From in silico to in Vitro to In Vivo: Increasing Megakaryocytes to Treat Thrombocytopenia

Hematopoietic stem cells undergo a multi-step differentiation program through several precursor stages to give rise to megakaryocytes (Mk), which ultimately release platelets. Thrombocytopenia can manifest in various clinical settings and can adversely affect a patient's quality of life through easy bruising and risk of bleeding. An example is chemotherapy-induced thrombocytopenia (CIT) which occurs when myelosuppressive chemotherapy is given, especially with certain agents such as platinum analogs and cyclophosphamide. We used a single-cell RNA-sequencing approach to study the differentiation of hematopoietic stem cells to Mk progenitors (MkP) and delineated the trajectory that defines the transition of cells to the megakaryocytic lineage. Using our proprietary platform which pairs new approaches in computation and machine learning in drug discovery, we predicted small molecule interventions that could modulate the hematopoietic lineage direction to increase the differentiation towards MkP and subsequent increases in platelet counts. Using an in vitro 5-day CD34-based Mk differentiation assay we demonstrated that some of our predicted interventions increased generation of MkP from stem cells. Analysis of early MkP (CD34-CD235a-CD71+CD41b+CD42b-) and late MkP (CD34-CD235a-CD71-CD41b+CD42b+) by flow cytometry elucidated differential mechanisms of action such as induction of early or late MKP or both. We performed an 8-day study in healthy mice, which revealed that a selected set of compounds increased MkPs in vivo, consistent with our predicted cell behavior and in vitro findings. To evaluate a possible application for this MkP and platelet increases we tested the efficacy of one of our hit compounds CP3 in a CIT mouse model using Carboplatin. In this model, we recorded a &amp;gt;70 % reduction in platelet counts on day 9 post carboplatin administration, with platelet numbers recovering on day 13 and return to basal levels by day 21. To assess the efficacy of CP3, mice dosed first with this compound were challenged with carboplatin. The primary endpoint of this study was the ability of the compound to rescue mice from nadir of thrombocytopenia and accelerate recovery to baseline. Prior to carboplatin dosing, 7 days of CP3 dosing showed a dose dependent increase in platelet counts confirming our initial studies. However, CP3 dosing did not rescue platelet nadir or accelerate recovery to baseline in the CIT model. This study demonstrated the capacity of CP3 to increase platelets in a healthy BM environment but not under conditions of myelosuppression as seen in the CIT mouse model. Taken together, these findings highlight the benefits of our platform to predict compounds that modulate lineage differentiation towards MkP, and a resultant increase in platelet numbers in an animal model.

Efficacy and Safety of Avatrombopag on Thrombocytopenia after Chemotherapy in Acute Leukaemia

Background: Thrombocytopenia following chemotherapy is a common and serious complication that leads to an increased risk of bleeding and poor prognosis for patients with acute leukaemia. Current therapeutic strategies consist of platelet transfusion, recombinant human interleukin-11(rhIL-11) and recombinant human thrombopoietin (rhTPO) injection, but these strategies are not satisfactory for some patients and the treatment remains challenging. Avatrombopag is a novel thrombopoietin receptor agonist, which had been approved for thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a surgery in the USA, Europe, and China, and in patients with chronic immune thrombocytopenia who were unresponsive to previous treatments in the USA and Europe. This study aims to determine the efficacy and safety of avatrombopag on thrombocytopenia after chemotherapy of acute leukaemia, and to increase the evidence for clinical use of avatrombopag. Methods: The clinical data of 24 acute leukaemia patients with grade 3/4 chemotherapy-induced thrombocytopenia (CIT) for 3-28 days were collected from February 2022 to February 2023. All patients received avatrombopag orally at a dose of 40 mg / day. Platelet (PLT) transfusion was allowed when the platelet level was less than 20×10 9/L or with bleeding events. If platelet count increased to 100 ×10 9/L or 50 ×10 9/L more than baseline, which was defined as complete response (CR), treatment of avatrombopag was stopped. Results: The median age of 24 patients with CIT was 38 (range 17‒69) years, with 14 patients diagnosed with acute myeloid leukemia (AML), 9 patients diagnosed with acute lymphoblastic leukemia (ALL), and 1 patient diagnosed with mixed phenotype acute leukemia (MPAL). Chemotherapy regiments for patients with AML included decitabine combined with venetoclax (n=5), decitabine combined with arabinoside (n=3), arsenic trioxide combined with retinoic acid (n=3), azacytidine combined with venetoclax (n=2), azacytidine combined with medium-dose arabinoside (n=1). Chemotherapy regiments for patients with ALL included CD19 specific CAR-T cells (n=3), decitabine (n=2), blinatumomab (n=2), IVP (idarubicin, vindesine, and prednisone) (n=1), azacytidine combined with venetoclax and chidamide (n=1). Chemotherapy regiment for the patient with MPAL was decitabine combined with venetoclax (n=1). At baseline, 10 patients experienced grade 3 thrombocytopenia after chemotherapy, while 14 patients experienced grade 4 thrombocytopenia after chemotherapy. The median lowest platelet count was 19×10 9/L (range 1-47×10 9/L). During the treatment period, 14 patients received platelet transfusion. The median time to reach the CR standard was 6 (range 3-26) days, and no patients stopped treatment due to side effect or drug intolerance. Compared with using avatrombopag before, the levels of platelet count were significantly increased ( P=0.000 1). The optimal platelet count of 22 patients reached the standard of CR after 7 days of drug withdrawal. Conclusion: Avatrombopag is effective on increasing platelet counts in patients with acute leukaemia after chemotherapy, with a good safety profile. It is a suitable therapeutic option for thrombocytopenia after chemotherapy.

Effectiveness and Safety of Hetrombopag in the Management of Radiotherapy-Induced Thrombocytopenia in Patients with Gynecological Malignancies

Background: Radiotherapy is a cornerstone of treatment strategies for gynecological malignancies, However, while effective against neoplastic cells, pelvic radiotherapy frequently incurs collateral damage to normal tissues, especially to the bone marrow. This unintended consequence often precipitates thrombocytopenia, a condition characterized by diminished platelet levels, thereby elevating the risk of bleeding and posing hurdles for the continuity of anticancer regimens. Addressing this clinical challenge, hetrombopag, an innovative, orally administered non-peptide thrombopoietin receptor agonist, presents promise. It works by kindling megakaryocyte proliferation and differentiation, thereby enhancing platelet production via the activation of thrombopoietin receptor dependent STAT and MAPK signaling pathways. Previous studies have documented its efficacy in expediting platelet recovery in patients with chemotherapy-induced thrombocytopenia, thereby curtailing the duration of the condition and ensuring the execution of planned chemotherapy cycles. This study aims to investigate the therapeutic effectiveness and safety profile of hetrombopag in the treatment of radiotherapy-induced thrombocytopenia within a real-world context. Methods: This retrospective study encompassed gynecological cancer patients who developed thrombocytopenia (platelet counts&amp;lt;100×10 9/L) following radiotherapy and subsequently underwent treatment with hetrombopag from January 2022 to June 2023. The key inclusion criteria included an age of ≥18 years, the development of thrombocytopenia after radiotherapy or a combination of radiotherapy and other anticancer interventions, the administration of hetrombopag as monotherapy or as part of a combined regimen with other platelet-boosting agents, and the availability of follow-up data. The primary efficacy outcome was the proportion of patients exhibiting a platelet response (an elevation in platelet counts to ≥75×10 9/L) within 14 days. Results: Our cohort consisted of 28 gynecological cancer patients, encompassing 21 (75.0%) cases of cervical cancer, 3 (10.7%) of endometrial cancer, 1 (3.6%) of ovarian cancer, and 3 (10.7%) of other gynecological malignancies. The patients' median age was 58 years (range: 29-76 years), with 50% in clinical stage III/IV. Among them, 19 had received radiotherapy, 8 had undergone concurrent chemoradiotherapy, and 1 had received radiotherapy plus targeted therapy and immunotherapy. The baseline platelet count prior to hetrombopag treatment was 54.1±16.5×10 9/L. Hetrombopag was administered at a dose of 2.5mg/day as monotherapy in 32.1% of patients and combined with recombinant human thrombopoietin or recombinant human interleukin 11 in 67.9% of patients. The observed platelet response rate was 53.6% within 7 days and increased to 75.0% by the 14-day mark. The median time to platelet response was 7 days (95% confidence interval: 5-14). Following the introduction of hetrombopag as monotherapy or part of a combination regimen, we noted a steady uptick in patients' platelet counts. The mean platelet counts on days 3, 5, 7, 9, 11, and 14 were 62.3, 74.9, 78.7, 88.3, 87.9, and 147.9 ×10 9/L, respectively (Figure). Throughout the treatment period, no adverse events related to hetrombopag were reported. Conclusion: In conclusion, our findings provide preliminary evidence for the effectiveness and safety of hetrombopag, administered either as monotherapy or in combination, for managing radiotherapy-induced thrombocytopenia. Given the retrospective design of this study, further corroboration is needed through large-scale, prospective, randomized, and controlled clinical trials.

Novel Combination of Erythropoietin and Romiplostim to Treat Chemotherapy-Induced Anemia and Thrombocytopenia via Pharmacodynamic Interaction on Hematopoietic Stem and Progenitor Cells

Novel Combination of Erythropoietin and Romiplostim to Treat Chemotherapy-Induced Anemia and Thrombocytopenia via Pharmacodynamic Interaction on Hematopoietic Stem and Progenitor Cells

Disparities in the consensus for treatment of chemotherapy-induced thrombocytopenia.

Chemotherapy-induced thrombocytopenia (CIT) is an arduous complication of chemotherapy to be dealt with, and there are many unmet needs in this field to be addressed on the global front. We have conducted this study to contribute to the understanding of existing knowledge gaps of CIT management and highlight the direction to focus future investigations. This was an academic single-institution report on a cross-sectional study evaluating CIT management practices using platelet (PLT) transfusions by haematologists and oncologists in Armenia. Physicians' opinions differed significantly when it came to defining thrombocytopenia by PLT levels. 13.2% of those surveyed considered thrombocytopenia to be when PLT counts fall below 180 × 109/L, 42.1% defined thrombocytopenia to have a PLT threshold of 150 × 109/L, 15.8% and 21.0% specialists setting their thresholds at 140 × 109/L and 100 × 109/L, respectively.All physicians managed CIT by performing PLT transfusions for prophylactic purposes (i.e., when PLT count falls below a certain threshold) with none of them transfusing PLTs only on-demand to address active bleeding. 73.3% haematologists (adult), 57.1% medical oncologists, and 50% paediatricians deemed 10 × 109/L as the threshold PLT count for transfusing afebrile patients with haematologic malignancies (besides acute promyelocytic leukaemia (APL)) and solid tumours.PLT products availability varied among the respondents, with only 53% of them responding that they had 24/7 access. CIT is a complication of interest to physicians worldwide and has not been resolved yet. This is the first conducted survey regarding CIT and the initial step for further research.

Treatment of chemotherapy-induced thrombocytopenia with monotherapy versus combination therapy: the devil is in the details

Treatment of chemotherapy-induced thrombocytopenia with monotherapy versus combination therapy: the devil is in the details

Hetrombopag plus recombinant human thrombopoietin for chemotherapy-induced thrombocytopenia in patients with solid tumors

BackgroundChemotherapy-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). ObjectivesThis multicenter retrospective cohort study aimed to evaluate the efficacy and safety of hetrombopag plus rhTPO compared with rhTPO alone for CIT. MethodsA 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. ResultsOne 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. ConclusionCompared to rhTPO alone, our findings suggest that the combination of hetrombopag and rhTPO is safe and more effective in patients with CIT.

P15 Use of romiplostim in chemotherapy-induced thrombocytopenia in gynecologic and breast cancers

P15 Use of romiplostim in chemotherapy-induced thrombocytopenia in gynecologic and breast cancers

A retrospective study on the efficacy and safety of avatrombopag in the treatment of chemotherapy-induced thrombocytopenia in gastrointestinal cancer.

e16334 Background: Chemotherapy-induced thrombocytopenia (CIT) is defined as post-chemotherapy platelets count &lt; 100×109/L. Avatrombopag is an oral thrombopoietin receptor to treat thrombocytopenia. Although many factors lead to an increased risk of CIT in gastrointestinal cancer, there is currently no targeted research. This study aimed to investigate the efficacy and safety of avatrombopag for CIT in gastrointestinal cancer. Methods: This multicenter, retrospective study included adult gastrointestinal cancer patients with CIT who received avatrombopag treatment (40mg/60mg, 5 days) between September 2020 and February 2022. The patient meets one of the following conditions were included in this study: a) Platelet count &lt;100×109/L before receiving avatrombopag treatment in the current chemotherapy cycle, and platelet count &lt;50×109/L in the last cycle; b) Platelet count &lt;75×109/L before receiving avatrombopag treatment in the current chemotherapy cycle. The main endpoint was the proportion of patients with platelet count &gt;100×109/L or platelet count increased by &gt;50×109/L or platelet count increased by &gt; 100% in the cycle after the start of avatrombopag therapy. Results: 58 patients were included in this study. 53.40%, 82.80%, and 96.6% of the patients reached the effective endpoint after 5±2, 11±3, and 18±3 days of avatrombopag treatment, respectively. No drug toxicity related to avatrombopag was found in this study. No significant influencing factors of effective rate were found. And there was no significant difference was found among the effective rate and platelet transfusion rate of avatrombopag (AVA), AVA+Recombinant Human Interleukin-11 (rhIL-11), and AVA+Recombinant Human Thrombopoietin (rhTPO). However, compared with AVA+IL-11, the AVA+rhTPO group had lower baseline platelet counts. And the mean of increasing platelet counts on the 5±2 (41.32×109/L vs. 37.00×109/L) and 11±3 day (110.94×109/L vs. 84.00×109/L) were better in the AVA+rhTPO group, though not significantly. Conclusions: Avatrombopag has high efficacy and safety in the treatment of CIT in gastrointestinal cancer. rhTPO rather than rhIL-11 combined with avatrombopag may be more suitable for patients with low baseline platelet counts. [Table: see text]

Thrombopoietin receptor agonist antibody for treating chemotherapy-induced thrombocytopenia

BackgroundThrombocytopenia is a common complication in cancer patients undergoing chemotherapy. Chemotherapy-induced thrombocytopenia (CIT) leads to dose reduction and treatment delays, lowering chemotherapy efficacy and survival rate. Thus, rapid recovery and continuous maintenance of platelet count during chemotherapy cycles are crucial in patients with CIT. Thrombopoietin (TPO) and its receptor, myeloid proliferative leukemia (MPL) protein, play a major role in platelet production. Although several MPL agonists have been developed to regulate thrombopoiesis, none have been approved for the management of CIT due to concerns regarding efficacy or safety. Therefore, the development of effective MPL agonists for treating CIT needs to be further expanded.MethodsAnti-MPL antibodies were selected from the human combinatorial antibody phage libraries using phage display. We identified 2R13 as the most active clone among the binding antibodies via cell proliferation assay using BaF3/MPL cells. The effect of 2R13 on megakaryocyte differentiation was evaluated in peripheral blood CD34+ cells by analyzing megakaryocyte-specific differentiation markers (CD41a+ and CD42b+) and DNA ploidy using flow cytometry. The 2R13-induced platelet production was examined in 8- to 10-week-old wild-type BALB/c female mice and a thrombocytopenia mouse model established by intraperitoneal injection of 5-fluorouracil (150 mg/kg). The platelet counts were monitored twice a week over 14 days post-initiation of treatment with a single injection of 2R13, or recombinant human TPO (rhTPO) for seven consecutive days.ResultsWe found that 2R13 specifically interacted with MPL and activated its signaling pathways. 2R13 stimulated megakaryocyte differentiation, evidenced by increasing the proportion of high-ploidy (≥ 8N) megakaryocytes in peripheral blood-CD34+ cells. The platelet count was increased by a single injection of 2R13 for up to 14 days. Injection of 5-fluorouracil considerably reduced the platelet count by day 4, which was recovered by 2R13. The platelets produced by 2R13 sustained a higher count than that achieved using seven consecutive injections of rhTPO.ConclusionsOur findings suggest that 2R13 is a promising therapeutic agent for CIT treatment.