Chemotherapy-induced Thrombocytopenia In Patients Research Articles

Effectiveness of partial splenic embolization in colorectal cancer patients with chemotherapy-induced thrombocytopenia: results of a single institution retrospective study

ObjectiveTo evaluate the safety and efficacy of partial splenic embolization (PSE) in treating chemotherapy-induced thrombocytopenia (CIT) in patients with colorectal cancer who failed to respond to platelet growth factor therapy.Methods56 patients who underwent PSE were retrospectively analyzed. Based on the inclusion and the exclusion criteria, 29 patients were eligible for the study, of whom one underwent twice PSE procedures due to recurrent thrombocytopenia. The clinical characteristics were retrospectively analyzed with respect to efficacy, safety and outcome.Results60.0% of patients restarted antineoplastic therapy after PSE. There was a positive correlation between difference value of platelet count and embolization material size (Eta Squared = 0.252, p < 0.05). The correlation between the absolute volume of spleen embolized and postoperative complications was analyzed, with a statistically significant result (p < 0.001). The mean preoperative spleen volume, the preoperative platelet count, postoperative platelet count and difference value of platelet count in the non-cirrhotic group were larger than those in the cirrhotic group (p < 0.001). The mean overall survival was 47.7 ± 7.7 months.ConclusionPSE is safe and effective in the treatment of CIT patients with colorectal cancer. The larger the embolized particle, the more platelets grew. The severity of complication was also positively correlated with the absolute volume of spleen embolized. Therefore, large particle embolization materials can be used to improve the efficacy of PSE and reduce complications. For CIT patients with cirrhosis, PSE was less effective in improving platelet count than those without cirrhosis.

Thrombopoietin improves the functions of bone marrow endothelial progenitor cells via METTL16/Akt signalling of haematological patients with chemotherapy-induced thrombocytopenia.

Bone marrow endothelial progenitor cells (BM EPCs) are crucial in supporting haematopoietic regeneration, while the BM EPCs of haematological patients with chemotherapy-induced thrombocytopenia (CIT) are unavoidably damaged. Therefore, the present study aimed to examine the effect of thrombopoietin (TPO) on the recovery of BM EPCs of CIT patients and to identify the underlying mechanisms. The cell functions were determined by 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (Dil)-acetylated low-density lipoprotein (Dil-Ac-LDL) uptake and fluorescein isothiocyanate (FITC)-labeled Ulex europaeus agglutinin-I (FITC-UEA-I) binding assay, as well as proliferation, migration and tube formation experiments. Endothelial cells were transfected with METTL16 lentivirus, followed by methylated RNA immunoprecipitation sequencing. Zebrafish with vascular defect was used as the invivo model. TPO significantly improved the quantity and functions of BM EPCs from CIT patients invitro and restored the subintestinal vein area of zebrafish with vascular defect invivo. Mechanically, TPO enhanced the BM EPC functions through Akt signal mediated by METTL16, which was downregulated in BM EPCs of CIT patients and involved in the regulation of endothelial functions. The present study demonstrates that TPO improves the recovery of BM EPCs from CIT patients with haematological malignancies via METTL16/Akt signalling, which provides new insights into the role of TPO in treating CIT in addition to direct megakaryopoiesis.

Clinical observation study of recombinant human thrombopoietin in the prevention of chemotherapy-induced thrombocytopenia in patients with aggressive lymphoma.

e19056 Background: Recombinant human thrombopoietin (rhTPO) has demonstrated efficacy in elevating platelet counts in lymphoma patients suffering from chemotherapy-induced thrombocytopenia. However, the optimal timing for its administration remains to be established. Methods: This prospective, observational, non-randomized, multicenter study aimed to identify the optimal timing for rhTPO intervention in patients with aggressive lymphoma experiencing chemotherapy-induced thrombocytopenia. Participants aged between 18 and 70 years, diagnosed with aggressive lymphoma and chemotherapy-induced thrombocytopenia, were divided into three groups based on their baseline platelet counts. Group 1 received rhTPO when platelet counts fell below 50×109/L but remained above 25×109/L; Group 2 was treated with rhTPO at platelet counts ≥ 50×109/L and < 75×109/L; and Group 3 received rhTPO treatment for platelet counts ≤ 25×109/L. Treatment was discontinued once platelet counts reached ≥ 100×109/L. The primary endpoint was the proportion of patients achieving normalization of platelet counts, the secondary outcomes including platelet nadir values, the incidence of platelet transfusions, and adverse events. Results: Eighty-eight patients were enrolled, with 36 in Group 1, 22 in Group 2, and 30 in Group 3. The groups were comparable in clinical manifestation of age, gender, comorbidities, lymphoma classification, and bone marrow involvement. Normalization of platelet counts was achieved in 69.44%, 81.82%, and 36.67% of patients in Groups 1, 2, and 3, respectively, with Groups 1 and 2 showing significantly higher rates than Group 3 (P<0.05). The mean platelet nadir values were significantly higher in Groups 1 and 2 (28.39±10.19×109/L and 43.23±14.97×109/L, respectively) compared to Group 3 (11.13±6.21×109/L, P<0.01). The incidence of platelet transfusions was notably lower in Groups 1 and 2 (19.44% and 13.64%, respectively) than in Group 3 (70.00%, P<0.01). There were no significant differences in adverse event rates across the groups. Conclusions: Early administration of rhTPO significantly enhances platelet recovery and reduces the need for platelet transfusions in aggressive lymphoma patients with chemotherapy-induced thrombocytopenia.

A phase I clinical study to evaluate the safety, tolerability, immunogenicity, pharmacokinetics and preliminary efficacy of SCB-219M in patients with chemotherapy-induced thrombocytopenia (CIT): An interim analysis.

e15015 Background: CIT is a serious, chemotherapy-associated complication observed in a wide range of cancer patients with various types of cancer. Incidence of CIT can occur in about 15-25% of patients undergoing standard chemotherapy regiments with platinum, taxane and/or gemcitabine-based regimen. CIT can lead to chemotherapy dose delay or dose reduction, and potentially bleeding events. Currently, there is no FDA-approved therapy for CIT. SCB-219M, a thrombopoietin receptor agonist (TPO-RA) mimetic bispecific Fc-fusion protein produced from CHO cells can efficiently raise PLT count under normal and pathological conditions in laboratory animals. Methods: This is a single-arm, multi-center, open-label, dose escalation Phase Ia clinical study to evaluate the safety, tolerability, and immunogenicity, PK profile and preliminary efficacy of a single ascending dose of SCB-219M administered one day after a chemotherapy in prior CIT patients with malignant solid tumors and lymphoma. The study design of accelerated titration combined with "3 + 3" is used, and the number of subjects planned to enroll is 12 to be assigned to 4 cohorts with 2, 6, 10 and 15 mg/kg subcu administration of SCB-219M, respectively. Enrollment criteria include episode of CIT experienced (<75 × 109/L in PLT count) in prior cycle of chemotherapies and PLT count has recovered to >75 × 109/L prior to initiation of this study . The chemotherapy regimen allowed include either mono or combination chemotherapy (including targeted therapy and/or immunotherapy). The observation period of dose-limiting toxicities (DLTs) is 21 days. Chemotherapy is planned at each study site. There will be no change in the planned dose or frequency of chemotherapy in the study. Results: As of Dec 20, 2023, 9 prior CIT patients including 3 at 15 mg/kg were enrolled. SCB-219M was well tolerated. There were no SAEs or AESIs (Adverse Event of Special Interest) observed. DLT was not reached. A favorable PK profile, in particular in serum availability (AUC) and half-life (T1/2) was obtained. All 9 prior CIT patients in the study maintained PLT counts >75 x 109/L from 1-week following chemotherapies with a single dose of SCB-219M, and durable responses experienced through at least 3 weeks. Conclusions: In this interim analysis, drug safety, PK profile and durable efficacy are expected to support SCB-219M dosing interval of ≥2-weeks or a single dosing regimen within a chemotherapy cycle. Accordingly, a Phase Ib trial evaluating repeated dosing of SCB-219M is planned to initiate in 2024. Clinical trial information: NCT05426369 .

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

PurposeThrombocytopenia 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.MethodsClinical 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.ResultsUnivariate 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.ConclusionThe 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.

Hetrombopag for the management of chemotherapy-induced thrombocytopenia in patients with advanced solid tumors: a multicenter, randomized, double-blind, placebo-controlled, phase II study.

Chemotherapy-induced thrombocytopenia (CIT) increases the risk of bleeding, necessitates chemotherapy dose reductions and delays, and negatively impacts prognosis. This study aimed to evaluate the efficacy and safety of hetrombopag for the management of CIT in patients with advanced solid tumors. A multicenter, randomized, double-blind, placebo-controlled, phase II study. Patients with advanced solid tumors who experienced a chemotherapy delay of ⩾7 days due to thrombocytopenia (platelet count <75 × 109/L) were randomly assigned (1:1) to receive oral hetrombopag at an initial dose of 7.5 mg once daily or a matching placebo. The primary endpoint was the proportion of treatment responders, defined as patients resuming chemotherapy within 14 days (platelet count ⩾100 × 109/L) and not requiring a chemotherapy dose reduction of ⩾15% or a delay of ⩾4 days or rescue therapy for two consecutive cycles. Between 9 October 2021 and 5 May 2022, 60 patients were randomized, with 59 receiving ⩾1 dose of assigned treatment (hetrombopag/placebo arm, n = 28/31). The proportion of treatment responders was significantly higher in the hetrombopag arm than in the placebo arm [60.7% (17/28) versus 12.9% (4/31); difference of proportion: 47.6% (95% confidence interval (CI): 26.0-69.3); odds ratio = 10.44 (95% CI: 2.82-38.65); p value (nominal) based on the Cochran-Mantel-Haenszel: <0.001)]. During the double-blind treatment period, grade 3 or higher adverse events (AEs) occurred in 35.7% (10/28) of patients with hetrombopag and 38.7% (12/31) of patients on placebo. The most common grade 3 or higher AEs were decreased neutrophil count [35.7% (10/28) versus 35.5% (11/31)] and decreased white blood cell count [17.9% (5/28) versus 19.4% (6/31)]. Serious AEs were reported in 3.6% (1/28) of patients with hetrombopag and 9.7% (3/31) of patients with placebo. Hetrombopag is an effective and well-tolerated alternative for managing CIT in patients with solid tumors. ClinicalTrials.gov identifier: NCT03976882.

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.

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.

Dietary ketone body-escalated histone acetylation in megakaryocytes alleviates chemotherapy-induced thrombocytopenia.

Chemotherapy-induced thrombocytopenia (CIT) is a severe complication in patients with cancer that can lead to impaired therapeutic outcome and survival. Clinically, therapeutic options for CIT are limited by severe adverse effects and high economic burdens. Here, we demonstrate that ketogenic diets alleviate CIT in both animals and humans without causing thrombocytosis. Mechanistically, ketogenic diet-induced circulating β-hydroxybutyrate (β-OHB) increased histone H3 acetylation in bone marrow megakaryocytes. Gain- and loss-of-function experiments revealed a distinct role of 3-β-hydroxybutyrate dehydrogenase (BDH)-mediated ketone body metabolism in promoting histone acetylation, which promoted the transcription of platelet biogenesis genes and induced thrombocytopoiesis. Genetic depletion of the megakaryocyte-specific ketone body transporter monocarboxylate transporter 1 (MCT1) or pharmacological targeting of MCT1 blocked β-OHB-induced thrombocytopoiesis in mice. A ketogenesis-promoting dietalleviated CIT in mouse models. Moreover, a ketogenic diet modestly increased platelet counts without causing thrombocytosis in healthy volunteers, and a ketogenic lifestyle inversely correlated with CIT in patients with cancer. Together, we provide mechanistic insights into a ketone body-MCT1-BDH-histone acetylation-platelet biogenesis axis in megakaryocytes and propose a nontoxic, low-cost dietary intervention for combating CIT.

Efficiency and Safety of Avatrombopag in the Management of Thrombocytopenia with TPO or Tpora Ineffective：a Prospective, Single Arm, Exploratory Clinical Study

Thrombocytopenia refers to the sum of a series of clinical diseases with a platelet count of less than 100×109/L in peripheral blood, including primary immune thrombocytopenia (ITP), tumor chemotherapy-related thrombocytopenia (CIT), infection, etc. The traditional treatments of thrombocytopenia are not always effective and often lead to serious side effects. Therefore, thrombopoietin (TPO) and TPO receptor agonist (TPORA) have been found to play a role as early recombinant thrombopoietin and gradually become a new alternative treatment. At present, there are few studies on the treatment of thrombocytopenia with Avatrombopag, as a second-generation TPORA, at home and abroad. We designed a prospective, single arm, exploratory clinical study to evaluate the efficacy and safety of Avatrombopag in the treatment of thrombocytopenia with TPO or TPORA ineffective. The patients with platelet counts less than 25×109/L who have failed to respond to TPO or other TPORA (including Eltrombopag，Herombopag) treatment in the Fourth Affiliated Hospital of Medical College of Zhejiang University were recruited. All the eligible patients were administered oral Avatrombopag at an initial dose of 20mg/d or 40 mg/d, monitored complete blood count at least once a week, and adjusted the drug dose according to the platelet level. The efficacy and safety of the drug were analyzed by monitoring the changes of platelet level and bleeding grade within 4 weeks after treatment, and the adverse reactions of Avatrombopag. This study was registered at chictr.org.cn (ChiCTR2200061853). 22 patients were enrolled in the clinical trial, aged from 18 to 83 years, with a median age of 74 years, including 16 patients with immune thrombocytopenia (ITP), 5 patients with chemotherapy-induced thrombocytopenia (CIT) and one patient with thrombocytopenia caused by MDS. Baseline characteristics of patients enrolled in the study are shown in Table 1. During 4-w Avatrombopag treatment period, the median platelet count in ITP group was higher than that in CIT group (Table 2 and Figure 1). 20 patients (90.9%) had bleeding symptoms at baseline, which decreased to 36.4% (8/22) in the end of follow-up (Figure 2). After 4 weeks of treatment, 17 patients showed response to the drug (platelet count between 30 and 100×109/L, at least doubling of the baseline count, and absence of bleeding), with a median response time of 14 (5-27) days. Among them, 13 patients were ITP, 3 patients were CIT, and 1 patient was MDS-induced-thrombocytopenia. The difference was not statistically significant (p=0.654). 9 patients achieved complete response (platelet count higher than 100×109/L and absence of bleeding), all of them were ITP. Compared with CIT patients, the difference was statistically significant (p=0.045) (Table 3 and Figure 3). 20 of 22 patients (90.9%) no longer required platelet transfusion at the study end point. During the administration period, one patient was found to have mild liver dysfunction that is difficult to explain by other diseases, and the other patients were not found to have drug-related adverse effects. In conclusion, Avatrombopag is an effective and safe drug for the treatment of patients with relapse and refractory thrombocytopenia. Compared with CIT patients, Avatrombopag have faster response to platelets and higher remission rate for ITP patients. he research was supported by the Key R&D Program of Zhejiang, No. 2022C03137; Public Technology Application Research Program of Zhejiang, China, No. LGF21H080003; the Key Project of Jinhua Science and Technology Plan, China, No. 2020-3-011; the 2019-2022 Key Medical Discipline (Hematology) Fund of Jinhua, China. Correspondence to : Dr Jian Huang, Department of Hematology, The First Affiliated Hospital of Zhejiang University School of Medicine. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Two Randomized Controlled Trials of Romiplostim for Chemotherapy-Induced Thrombocytopenia in Patients with Solid Tumors

Two Randomized Controlled Trials of Romiplostim for Chemotherapy-Induced Thrombocytopenia in Patients with Solid Tumors

Chemotherapy Dose Reductions and Dose Delays Due to Thrombocytopenia

Background: Chemotherapy-induced thrombocytopenia (CIT) is a challenging clinical scenario. A recent study of 15,521 patients showed that 13% of patients with solid tumors had thrombocytopenia within 3 months (Shaw, Eur J Haematol. 2021).Unfortunately, there are no guidelines for the management of CIT. Therefore, clinicians use strategies such dose reduction (DR) and/or dose delays (DD) to reduce the bleeding risk(Kuter, Haematologica. 2022). Although the incidence of CIT in various types of cancers and chemotherapeutic agents is known, studies showing an association between DR or DD and duration of CIT are lacking. It is known that DR and DD can increase mortality(Havrilesky, Crit Reviews in Onc/Hematology. 2015; Liutkauskiene, BMC Cancer. 2018). The association of cirrhosis and duration of thrombocytopenia in patients with CIT is also not well described. Therefore, we conducted a retrospective analysis to study the association between duration of thrombocytopenia and dose delays and reduction in patients with CIT. Methods: This study was approved by the Institutional Review Board. A retrospective analysis was performed using the electronic medical record (EMR) for adult patients who received chemotherapy for breast, GI, GU, and lung cancer from January 1st, 2016, to December 31st, 2020, at Rush University Cancer Center. Adult patients who developed thrombocytopenia during treatment (platelet count < 100 × 109 /L) were included in the study. Patients with thrombocytopenia preceding the initiation of chemotherapy were excluded. One hundred thirty-five patients met the study inclusion criteria. EMR were reviewed to collect data on DR and DD that had been clearly attributed to chemotherapy by the treating oncologist's documentation. Data for age at first thrombocytopenia (following treatment initiation), total duration of thrombocytopenia, presence of cirrhosis, and presence of liver metastasis was collected. Pearson's chi-square test and logistic regression were used to test the associations between duration of thrombocytopenia (grouped as <14 days or ≥ 14 days) and the proportion of patients who experienced at least one DR or DD. We similarly tested the association between thrombocytopenia duration and cirrhosis or liver metastasis. Results: First, we analyzed the association between DR, DD, and duration of thrombocytopenia. There was no statistically significant association between duration of thrombocytopenia and DR. However, we found that patients with DD had 4.1 times the odds of having increased duration of thrombocytopenia (≥ 14 days) compared to the patients without DD (OR = 4.1, 95% CI = 2.0 - 8.5, P-value = 0.0001). Then, we studied the association between DD and duration of thrombocytopenia in patients with cirrhosis or liver metastasis. We found that in this subset patients with DD had 3.9 times the odds of having thrombocytopenia duration ≥ 14 days compared to the patients without DD (OR = 3.9, 95% CI = 1.4 - 10.8, P-value = 0.008). We then looked at the association of having cirrhosis and liver metastasis on duration of thrombocytopenia. We found that there was no statistically significant association between presence of liver metastasis and duration of thrombocytopenia. However, patients with cirrhosis had 3.5 times the odds of having thrombocytopenia duration ≥14 days compared to patients without cirrhosis (OR = 3.5, 95% CI = 1.1 - 11.3, P-value = 0.03). Discussion: Our study shows that in patients with CIT, duration of thrombocytopenia impacts the risk of DD, especially in patients with either cirrhosis or liver metastasis. The finding of interest is that patients with cirrhosis have a 4-fold increased risk of developing longer duration of thrombocytopenia, which can lead to dose delays. This raises the question of whether patients with cirrhosis should be supported by thrombopoietin receptor agonists to treat the thrombocytopenia and prevent treatment delays. Thrombopoietin (TPO) receptor agonists such as Romiplostim are showing increasing promise in the treatment of CIT, and there are currently multiple active phase III trials underway with dose-reductions and dose-delays as clinical endpoints. Further research is needed to identify risk factors that can predict the development of CIT and to identify evidence-based platelet thresholds for TPO agonist usage in CIT patients.

Avatrombopag for the treatment of thrombocytopenia induced by chemotherapy in patients with solid tumors: A multicenter, open-label, single-arm trial.

Objective: To explore the effect and safety of avatrombopag for chemotherapy-induced thrombocytopenia (CIT). Methods: This multicenter, open-label, single-arm trial enrolled CIT patients in eight centers from October 2020 to April 2021. The participants received avatrombopag tablets 60 mg once a day for 5–10 days. The main endpoint was the proportion of patients with platelet count ≥100×109/L or increased by ≥ 50×109/L or increased by ≥ 100% in the cycle after the start of treatment. Results: Seventy-four participants were enrolled with a mean age of 59.8 ± 11.62.2% were males. The cumulative effective rate (any criteria) was 70.3% at 4 weeks. 42 (56.8%) achieved platelet count ≥100×109/L, 44 (59.5%) increased by ≥ 50×109/L, and 27 (36.5%) increase by ≥ 100% from baseline. The duration of grade III and IV platelet reduction was 4.2 ± 5.3 days. The time of PLT recovery to ≥75×109/L was 9.4 ± 6.6 days. The time of PLT recovery to ≥100×109/L was 10.2 ± 6.4 days. The platelet count nadir was 57.9 ± 45.3×109/L. The most common adverse events were nausea (8.1%), fatigue (5.4%), and abdominal pain (1.4%). There were no cases of fever, headache, or peripheral edema. Conclusion: Although it was a single-arm trial without a control group, the application of avatrombopag in patients with CIT can increase the platelet count of the patients compared with baseline. Avatrombopag is safe and tolerable. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04609891?term=04609891&draw=2&rank=1, identifier [NCT04609891]

Treatment of chemotherapy-induced thrombocytopenia in patients with non-hematologic malignancies.

Chemotherapy-induced thrombocytopenia (CIT) is a common complication of the treatment of non-hematologic malignancies. Many patient-related variables (e.g., age, tumor type, number of prior chemotherapy cycles, amount of bone marrow tumor involvement) determine the extent of CIT. CIT is related to the type and dose of chemotherapy, with regimens containing gemcitabine, platinum, or temozolomide producing it most commonly. Bleeding and the need for platelet transfusions in CIT are rather uncommon except in patients with platelet counts below 25x109/L in whom bleeding rates increase significantly and platelet transfusions are the only treatment. Nonetheless, platelet counts below 70x109/L present a challenge. In patients with such counts, it is important to exclude other causes of thrombocytopenia (medications, infection, thrombotic microangiopathy, post-transfusion purpura, coagulopathy and immune thrombocytopenia). If these are not present, the common approach is to reduce chemotherapy dose intensity or switch to other agents. Unfortunately decreasing relative dose intensity is associated with reduced tumor response and remission rates. Thrombopoietic growth factors (recombinant human thrombopoietin, pegylated human megakaryocyte growth and development factor, romiplostim, eltrombopag, avatrombopag and hetrombopag) improve pretreatment and nadir platelet counts, reduce the need for platelet transfusions, and enable chemotherapy dose intensity to be maintained. National Comprehensive Cancer Network guidelines permit their use but their widespread adoption awaits adequate phase III randomized, placebo-controlled studies demonstrating maintenance of relative dose intensity, reduction of platelet transfusions and bleeding, and possibly improved survival. Their potential appropriate use also depends on consensus by the oncology community as to what constitutes an appropriate pretreatment platelet count as well as identification of patient-related and treatment variables that might predict bleeding.

Avatrombopag for chemotherapy-induced thrombocytopenia in patients with non-haematological malignancies: an international, randomised, double-blind, placebo-controlled, phase 3 trial

Chemotherapy-induced thrombocytopenia is common and causes chemotherapy dose reductions or treatment delays, bleeding, and suboptimal oncological outcomes. We aimed to evaluate avatrombopag, a thrombopoietin receptor agonist that increases platelet counts, in patients with non-haematological cancer and platelet counts lower than 50 ×109 cells per L. In this randomised, double-blind, placebo-controlled, phase 3 study, patients aged 18 years or older at 71 hospitals or cancer treatment centres in China, Hungary, Poland, Russia, Serbia, Ukraine, and the USA and with ovarian, bladder, or lung cancer receiving chemotherapy who had severe thrombocytopenia were randomly assigned (2:1) to oral avatrombopag 60 mg or oral placebo once daily given 5 days before and after chemotherapy, with randomisation stratified by number of chemotherapy drugs used. Patients, investigators, and data collectors were masked to group allocation. Eligibility required two previous lines of chemotherapy or fewer, an ECOG performance status of 2 or less, and no previous history of chemotherapy-induced thrombocytopenia. The composite primary endpoint was the proportion of responders not requiring platelet transfusion or either a 15% or more chemotherapy dose reduction or a 4-day or more chemotherapy delay due to thrombocytopenia following study treatment until the start of the subsequent cycle. Analyses were done on the intention-to-treat and per protocol populations. Safety was analysed in all patients who received at least one dose of avatrombopag. The trial is registered with ClinicalTrials.gov, NCT03471078, and has been completed. Between Oct 12, 2018, and June 28, 2020, 122 patients were enrolled and randomly assigned to receive avatrombopag (n=82) or placebo (n=40). Median follow-up was 31 days (IQR 22-61). Similar proportions of patients reached the primary endpoint in the avatrombopag and placebo groups (intention-to-treat: 57 [70%, 95% CI 58-79] of 82 vs 29 [73%, 95% CI 56-85] of 40; difference -3·0% (95% CI -21·6 to 15·6); p=0·72; per protocol: 51 [85%, 95% CI 73-93] of 60 vs 27 [84%, 95% CI 67-95] of 32; 0·6% (95% CI -20·8 to 22·1); p=0·96). 15 (18%) of 82 patients had serious adverse events in the avatrombopag group and eight (20%) of 40 in the placebo group, of which thrombocytopenia was most common (4 [5%] of 82 and 4 [10%] of 40 patients). Common grade 3-4 treatment-emergent adverse events were neutropenia (22 [27%] of 82 and 16 [40%] of 40 patients), leukopenia (19 [23%] of 82 and 5 [13%] of 40), anaemia (16 [20%] of 82 and 9 [23%] of 40), and thrombocytopenia (16 [20%] of 82 and 14 [35%] of 40). Most adverse events were considered unrelated to study drug. No treatment-related deaths were reported. In this population of patients with non-haematological malignancies who are relatively chemotherapy naive, chemotherapy-induced thrombocytopenia treatment outcomes were similar between the avatrombopag and placebo groups. Given its safety and ability to augment platelet counts in patients with chemotherapy-induced thrombocytopenia, evaluation of avatrombopag in populations with more persistent chemotherapy-induced thrombocytopenia is warranted. Dova Pharmaceuticals, a Sobi company.

A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Avatrombopag for the Treatment of Chemotherapy-Induced Thrombocytopenia in Patients with Solid Tumors

Background: Chemotherapy-induced thrombocytopenia (CIT) is a common complication in cancer patients receiving myelosuppressive chemotherapy. Not only can it increase the risk of bleeding, but it also complicates cancer treatment due to chemotherapy delays, dose reductions, and discontinuation, potentially resulting in sub-optimal treatment outcomes. There are currently no FDA approved medications available to manage CIT in the US and Europe. While platelet transfusions are used to rescue patients with very low platelet levels, they are associated with risks of viral and bacterial infections. Avatrombopag is an orally administered thrombopoietin (TPO) receptor agonist that mimics the biologic effects of TPO, resulting in increased platelet production. Avatrombopag is approved for the treatment of thrombocytopenia in patients with chronic liver disease (CLD) scheduled to undergo a procedure, and in adults with chronic immune thrombocytopenia (ITP) that have had an insufficient response to a prior therapy. Pre-clinical data as well as clinical data in patients with CLD and ITP suggest that Avatrombopag is a promising candidate for treatment of thrombocytopenia of diverse etiologies, including CIT. Study design and method: This is a phase 3 randomized, double-blind, placebo-controlled, multi-national (United States, Russia, Ukraine, Poland, China, Serbia, Hungary), study evaluating the efficacy and safety of oral Avatrombopag for the treatment of CIT in 120 adult patients with NSCLC, SCLC, bladder, or ovarian cancer (NCT03471078). To be eligible for the study, patients must have experienced severe thrombocytopenia (platelet counts (PC) &amp;lt;50x109/L) during their current chemotherapy regimen (the qualifying cycle defined as "cycle X"), , and receiving a 21- or 28-day chemotherapy regimen including one or more of the following agents/class of agents: gemcitabine, 5-FU, carbo- or cisplatin, anthracyclines, or alkylating agents. Main exclusion criteria include history of chronic platelet or bleeding disorders, thrombocytopenia due to an etiology other than CIT, &amp;gt;2 prior lines of myelosuppressive chemotherapy, prior history of CIT (PC &amp;lt;75 x109/L) in the previous 6 mo , history of hematologic malignancies, known clinically significant acute or active bleeding within 7 days of screening andrecent history of significant cardiovascular disease. Eligible patients will be randomized in a 2:1 ratio to receive either 60 mg Avatrombopag or placebo once daily for 5 days prior to and for 5 days immediately after the subsequent chemotherapy dose (cycle X+1). Cycle X+2 is an observational period with no study drug administered. The primary endpoint is the proportion of patients not requiring a platelet transfusion, a chemotherapy dose reduction by ≥15% ordelay by ≥4 days due to thrombocytopenia. Secondary endpoints include duration of platelet count &amp;lt;50x109/L after Avatrombopag treatment and through chemotherapy treatment cycle X+2, change in platelet count from baseline (nadir) to cycle X+1 (nadir), proportion of patients who do not have clinically relevant bleeding after Avatrombopag treatment and through chemotherapy treatment cycle X+2, proportion of patients who do not receive a platelet transfusion after treatment with Avatrombopag and through chemotherapy treatment cycle X+2 and incidence of adverse events. The treatment effect will be tested between Avatrombopag and placebo using the Cochran-Mantel-Haenszel test, adjusting for number of eligible chemotherapy agents (1, or ≥2). The study will consist of three periods: the double-blind treatment period and observational period of appr 8 to 9 weeks, an optional open label extension period for cycle X+3 (which may continue until the patients' current chemotherapy regimen ends), and a long-term follow-up period of up to 5 years. Summary: The study aims to evaluate the efficacy of Avatrombopag, an orally administered thrombopoietic agent, in increasing platelet counts to avoid platelet transfusions, chemotherapy dose delays and dose reductions in patients with solid tumors and severe CIT. This study has recently concluded enrollment as of June 2020. Disclosures Tian: Dova Pharmaceuticals: Current Employment. Jamieson:Dova Pharmaceuticals: Current Employment.

Chemotherapy-induced thrombocytopenia and platelet transfusion in patients with diffuse large B-cell lymphoma.

BackgroundCurrently, the risk factors associated with chemotherapy-induced thrombocytopenia (CIT) in patients with diffuse large B-cell lymphoma (DLBCL) are still undefined. Our study aimed to analyze the effects of risk factors on thrombocytopenia and to identify the threshold for infusion platelets of CIT patients who have received platelet transfusions.MethodsWe conducted a retrospective analysis of 523 patients with DLBCL from 2011 to 2013. The clinical and demographic parameters were extracted, and the risk factors associated with CIT were analyzed. The threshold for platelet transfusions in DLBCL patients with a central venous catheter (CVC) was evaluated.ResultsA total of 227 (43.4%) DLBCL patients had thrombocytopenia, and 63 (12.0%) had thrombocytopenia without concomitant cytopenia. We found that the choice of chemotherapy regimen was positively correlated with thrombocytopenia (P<0.001). The chemotherapy regimens most likely to result in thrombocytopenia were dexamethasone, cytarabine, cisplatin (DHAP) (92.3%), isophosphamide, carboplatin, etoposide (ICE) (89.7%), gemcitabine, dexamethasone, cisplatin (GDP) (89.7%), gemcitabine, and oxaliplatin (Gemox) (69.0%). In addition to these, high lactate dehydrogenase (LDH) (P=0.004) and Ann Arbor stage III/IV (P=0.024) were determined to be risk factors leading to thrombocytopenia. Forty patients (17.6%) had transfused platelets, and all of them were placed in the CVC. The high-threshold group (platelet count ≤20×109/L had a significantly lower amount of platelet transfusions than the low-threshold group ≤10×109/L. The platelet transfusion amount was 1.44±0.77 vs. 2.05±1.13 (P=0.047), respectively.ConclusionsThe chemotherapy regimens of DHAP, ICE, GDP, and Gemox can easily lead to thrombocytopenia. A high level of LDH in the peripheral blood and Ann Arbor stage III/IV are also associated with risk factors for thrombocytopenia. A 20×109/L prophylactic platelet transfusion threshold value is safer, more effective, and thus a better choice for DLBCL patients with CVC.

Efficacy and safety of recombinant human interleukin-11 in the treatment of acute leukaemia patients with chemotherapy-induced thrombocytopenia: A systematic review and meta-analysis.

Current meta-analysis was conducted aiming to assess the efficacy and safety of recombinant human interleukin-11 (rhIL-11) in the treatment of acute leukaemia (AL) patients with chemotherapy-induced thrombocytopenia (CIT). We searched PubMed, Embase, Chinese National Knowledge Infrastructure database (CNKI), Cochrane Library, and Wan Fang Database on 4 July 2018. Ten randomized controlled trials (RCTs) and two observational studies were included, which involved 754 AL patients with CIT. Pooled analysis demonstrated that rhIL-11 was beneficial on CIT: recovery time of platelet count to 50×109 /L [weight mean difference (WMD)=-4.19 days; 95% CI: -5.01, -3.37], recovery time of platelet count to 100×109 /L (WMD=-4.45days; 95% CI: -4.85, -4.06), platelet transfusion volume (WMD=-6.14U; 95% CI: -9.20, -3.09), and the rate of haemorrhage (RR=0.46; 95% CI: 0.36 to 0.61). Most adverse events associated with rhIL-11 were mild to moderate. Our findings suggest that rhIL-11 is effective and safe in the treatment of CIT in patients with AL.

Chinese Herbal Medicine (Xiaoaiping) Injections for Chemotherapy-Induced Thrombocytopenia: A Randomized, Controlled, Multicenter Clinical Trial

Objectives: The study aims to evaluate the therapeutic efficacy and safety of Chinese herbal medicine (Xiaoaiping) injections for chemotherapy-induced thrombocytopenia (CIT) in nonsmall cell lung cancer (NSCLC) and gastric cancer.Design: A randomized, controlled, multicenter study from December 2013 to August 2015.Settings/Location: All patients are from China.Subjects: One hundred forty patients with either NSCLC or gastric cancer were enrolled in this trial.Interventions: The intervention group (n = 70) was given Xiaoaiping injections (1 dose/day for 10 days) with chemotherapy, whereas the control group (n = 70) was given chemotherapy only. The follow up period was 11 days after the final injection.Outcome measures: Platelet (PLT) count was tested at day 0, 7, 14, and 21 as the primary outcome for evaluation. Safety measurements, including red blood cells (RBC), hemoglobin (HBG), white blood cells (WBC), neutrophil (NE)#, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), creatine kinase (CK), creatinine (Cr), and blood urea nitrogen (BUN) were tested at day 0 and 21 as the secondary outcomes.Results: (1) Two patients in the intervention group and four patients in the control group were lost upon follow-up. (2) PLT count: there was no significant difference in PLT count between the two groups from baseline (day 0), day 7, and day 14. At day 21, the intervention group indicated an upward trend of PLT count with a statistically significant difference than that of the control group (p < 0.05). (3) NSCLC: there was significant difference in PLT count between the two groups on day 21 (p < 0.01). (4) Gastric cancer: there was no significant difference in PLT count between the two groups during this trial (p > 0.05). (5) There was no statistically significant difference between the intervention group and the control group with the safety figures (secondary outcomes) RBC, HGB, WBC, NE#, AST, ALT, LDH, CK, Cr, and BUN measured (p > 0.05). (6) Adverse events: one gastric cancer patient in the control group was diagnosed with gastrointestinal bleeding on day 3.Conclusions: In conclusion, Xiaoaiping injections may provide a safe and effective option for CIT in patients with NSCLC.

Consensus on clinical diagnosis, treatment and prevention management of chemotherapy induced thrombocytopenia in China(2018)

Chemotherapy induced thrombocytopenia (CIT) is a common side-effect of chemotherapy in cancer patients, which lead to dose and cycle reduction or chemotherapy delay, or even the need of platelet transfusion. Therefore, CIT significantly increases the cost of treatment, reduces the efficacy of chemotherapy and the quality of life, and shortens the survival time of patients. The main treatments of CIT include transfusion of platelets, recombinant human thrombopoietin (rhTPO), and recombinant human interleukin-11 (rhIL-11). RhIL-11 is the first approved thrombocytopoietic cytokine. Interleukin-11 has been shown to be effective in the treatment of thrombocytopenia. RhTPO is a recombinant full-length glycosylated thrombopoietin, which is a ligand for c-Mpl protein. Several observations indicated that administration of rhTPO before and after chemotherapy might be beneficial to patients, which enhances platelet recovery and reduces thrombocytopenia after moderately myelosuppressive regimens. In recent years, the application of rhTPO in CIT treatment has dramatically changed the management and treatment plan of CIT. The China Society of Clinical Oncology (CSCO) published a consensus on CIT in 2014. Based on this, the expert committee updated "Consensus on clinical diagnosis, treatment and prevention management of chemotherapy induced thrombocytopenia in China (2018)" according to the recent literature and clinical research. The new evidence-based practice consensus for CIT aims to provide more reasonable diagnosis, treatment of prevention regimens for CIT patients to maintain the normal platelet counts.