Treatment Of Chemotherapy-induced Thrombocytopenia Research Articles

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<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<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.

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

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 < 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 <100×109/L before receiving avatrombopag treatment in the current chemotherapy cycle, and platelet count <50×109/L in the last cycle; b) Platelet count <75×109/L before receiving avatrombopag treatment in the current chemotherapy cycle. The main endpoint was the proportion of patients with platelet count >100×109/L or platelet count increased by >50×109/L or platelet count increased by > 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]

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.

351P Real-world study of herombopag in primary prevention and treatment of chemotherapy-induced thrombocytopenia (CIT) in advanced lung cancer

As is known to all, CIT generally begins 7 days after chemotherapy and reaches its lowest point at 10 days. This study investigated effectiveness and safety of primary prevention and treatment in patients with CIT after administration of Herombopag(a TPO-RA) in a real-world setting. The NCCN guidelines recommend that TPO-RA be considered in treating CIT. However, there is no clinical data on using Herombopag in primary prevention and treatment of CIT in advanced lung cancer.

Cost-effectiveness analysis of rhTPO and rhIL-11 in the treatment of chemotherapy-induced thrombocytopenia in hematological tumors based on real-world data

Chemotherapy-induced thrombocytopenia (CIT) is a common adverse reaction to chemotherapy that can lead to treatment delay, platelet transfusion, thereby increasing treatment costs, reducing chemotherapy effectiveness and affecting prognosis. Based on real-world data, this study analyzed the safety, efficacy, and economic of recombinant human thrombopoietin (rhTPO) and recombinant human interleukin-11 (rhIL-11) in the treatment of CIT in hematological tumors from the perspective of the health care system.We retrospectively collected the data of hematological tumor patients treated with rhTPO and rhIL-11 due to thrombocytopenia caused by chemotherapy. The propensity score matching (PSM) method was used to balance the baseline information of the two groups and they were further stratified according to the degree of thrombocytopenia (grade I-II and grade III-IV). The platelet compliance rate at 2 weeks of treatment was used as the efficacy evaluation index, and the cost-effectiveness method was used to evaluate the economic value of the two drugs in the treatment of thrombocytopenia based on drug effectiveness. Univariate and probabilistic sensitivity analyses were performed.A total of 1,571 patients met the inclusion and exclusion criteria, and 476 patients were included after 1:1 PSM. For patients with grade I-II thrombocytopenia, no significant difference in the platelet compliance rate was found between the two groups after 1 and 2 weeks of treatment. The platelet compliance rate in the rhTPO group was higher than that in the rhIL-11 group for patients with grade III-IV thrombocytopenia. Cost-effectiveness analysis (CEA) showed that the incremental cost-effectiveness ratio (ICER) for the rhTPO and rhIL-11 groups was 226,615.8. The ICER value was sensitive to the platelet compliance rate of the two groups, the cost of rhTPO, the cost of platelet transfusion in the rhTPO group. Probabilistic sensitivity analysis showed that when willingness to pay was less than approximately 220,000 yuan, rhIL-11 economy presented 100% better than that of rhTPO.In CIT treatment for hematological tumors, rhTPO yielded a higher platelet compliance rate than rhIL-11 treatment, especially for patients with grade III-IV thrombocytopenia. However, whether rhTPO has economic advantages still requires further exploration.

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.

NCCN Guidelines® Insights: Hematopoietic Growth Factors, Version 1.2022.

The NCCN Guidelines for Hematopoietic Growth Factors provide recommendations for the appropriate use of growth factors in the clinical management of febrile neutropenia (FN), chemotherapy-induced thrombocytopenia (CIT), and chemotherapy-induced anemia (CIA). Management and prevention of these sequelae are an integral part of supportive care for many patients undergoing cancer treatment. The purpose of these guidelines is to operationalize the evaluation, prevention, and treatment of FN, CIT, and CIA in adult patients with nonmyeloid malignancies and to enable the patient and clinician to assess management options for FN, CIT, and CIA in the context of an individual patient's condition. These NCCN Guidelines Insights provide a summary of the important recent updates to the NCCN Guidelines for Hematopoietic Growth Factors, with particular emphasis on the incorporation of a newly developed section on CIT.

Effect of avatrombopag in the management of severe and refractory chemotherapy-induced thrombocytopenia (CIT) in patients with solid tumors

Chemotherapy-induced thrombocytopenia (CIT) is a common complication in cancer patients, especially after multiple cycles of chemotherapy, which leads to the delayed treatment or reduced dosage. The treatment of CIT is limited for refractory and severe cases. Herein we reported a single-center study of avatrombopag, a type of thrombopoietin receptor agonist (TPO-RA), for the treatment of severe and refractory (S/R) CIT who failed from multi-line treatments. A total of 13 cancer patients with S/R CIT were enrolled at the First Affiliated Hospital of Zhejiang Chinese Medical University from September 2020 to February 2021. All the patients were administered oral avatrombopag at an initial dose of 60 mg/day, which could be decreased as needed, over a period of 8 weeks. Eight (8/13, 61.5%) patients responded to avatrombopag (with a platelet count ≥50 × 109/L and transfusion independent), with a median response time of 27.5 (11–50) days, and the median cumulative day of platelet response was 79 (20–167). Ten of 13 patients (76.9%) no longer required platelet transfusion at the study endpoint. The predictor of response was the level of hemoglobin (HB) at study entry, patients with an HB over 90 g/L achieved a response rate of 88.9%. In addition, platelet count showed 87.5% sensitivity and 100% specificity to predict the treatment response at a cutoff value of 25.5× 109/L at the end of the third week management. No drug-related side effects were noticed during administration. Our study showed that avatrombopag could be a novel and effective drug for the treatment of severe and refractory CIT, especially for those with hemoglobin above 90 g/L. This study was registered at chictr.org.cn as # ChiCTR2100050646.

A Case Study Using Papaya Leaf Extract to Reverse Chemotherapy-Induced Thrombocytopenia in a GBM Patient.

Chemotherapy-induced thrombocytopenia (CIT) is a critical condition in which platelet counts are abnormally reduced following the administration of chemotherapeutic compounds. CIT poses a treatment conundrum to clinicians given the increased risk of spontaneous bleeding, obstacles to surgical management of tumors, and exclusion from clinical trials. Treatment of CIT involves the removal of the offending agent combined with platelet infusion or thrombopoietin agonist treatment. However, due to the autoimmune and infection risks associated with infusions, this treatment is only reserved for patients with critically low platelet counts. One potential solution for patients in the mid to low platelet count range is Carica papaya leaf extract (CPLE). In this case, we report the novel use of CPLE as a method of bolstering platelet counts in a patient presenting with CIT. The patient was initiated on CPLE therapy consisting of 1 tablespoon twice daily with meals. Following CPLE treatment, the patient’s platelet counts rebounded from less than 10,000/µL to 113,000/µL. This clinical vignette supports the use of CPLE in the clinical context of CIT when thrombopoietin agonists are not a viable option. The potential benefits of CPLE as a method for increasing platelet count deserve further exploration, especially as a treatment option for refractory patients or those ill-suited for other traditional thrombocytopenia therapies.

Chemotherapy-induced thrombocytopenia in Ewing sarcoma: Implications and potential for romiplostim supportive care.

Maintaining dose-dense, interval-compressed chemotherapy improves survival in patients with Ewing sarcoma but is limited by myelosuppression. Romiplostim is a thrombopoietin receptor agonist that may be useful in the treatment of chemotherapy-induced thrombocytopenia (CIT). Patients aged between 3 and 33years with Ewing sarcoma from 2010 to 2020 were reviewed. CIT was defined as a failure to achieve 75,000 platelets per microliter by day 21 after the start of any chemotherapy cycle. Fisher's exact test was used for univariate analysis and Pearson's correlation coefficient was used for the association between continuous variables. Twenty-seven out of 42 patients (64%) developed isolated CIT, delaying one to four chemotherapy cycles per patient. CIT occurred during consolidation therapy in 24/27(88.9%) and with ifosfamide/etoposide cycles in 24/27 (88.9%). Univariate analysis failed to identify risk factors for CIT. The use of radiation approached significance (p-value=.056). Ten patients received romiplostim. The median starting dose was 3μg/kg (range 1-5). Doses were escalated weekly by 1-2 to 4-10μg/kg and continued throughout chemotherapy. A higher romiplostim dose was associated with a higher change in average platelet counts from baseline, r=.73 (p=.04). No romiplostim-related adverse events were identified aside from mild headache. CIT is the primary reason for the inability to maintain treatment intensity in Ewing sarcoma. The concurrent use of romiplostim with chemotherapy was safe and feasible, and efficacy was associated with higher romiplostim doses.

Efficacy and Safety of Extended Use of Romiplostim Treatment for Chemotherapy-Induced Thrombocytopenia

Background: Chemotherapy induced thrombocytopenia (CIT) is common, adversely impacts chemotherapy relative dose intensity, and may adversely impact cancer control. There is no approved therapy for CIT. In our recent phase II study of solid tumor patients with CIT (Soff et al, J. Clin. Onc., 2019), romiplostim lead to correction of platelet counts in 85% of participants within 3 weeks. While on romiplostim maintenance, only 6.8% of participants experienced chemotherapy dose reduction or delay as a result of recurrent CIT within a minimum of two cycles of chemotherapy or 8 weeks. However, there is a lack of long-term data on the efficacy and safety of romiplostim in CIT.Objectives: This is an extension analysis of the phase II study for patients receiving romiplostim maintenance for 12 months or longer.Patients/Methods: In the phase II study, 44 patients successfully met the primary endpoint of correction of their platelet count within 3 weeks and resumed chemotherapy with romiplostim maintenance. 21 patients (48%) remained on romiplostim for 12 months or longer. Data were collected from one month prior to initiation of romiplostim to one month after the last dose of drug. Data extracted included complete blood count, chemotherapy doses and dates, romiplostim doses and dates, body weight, cancer diagnosis, age, gender, date of death and thrombotic events. Efficacy was demonstrated by persistent maintenance of platelet counts during long-term chemotherapy and avoidance of episodes of reduced chemotherapy dose intensity. Safety was assessed by two methods: tracking the rates of venous or arterial thrombosis; as well as development of marrow fibrosis and/or secondary hematologic malignancy. The mean romiplostim doses and lab values are calculated by month of study participation.Results: All participants had metastatic disease. Breast (N=6) and colorectal (N=6) were the most common cancers. No participant discontinued romiplostim therapy due to an adverse event or futility. One patient received romiplostim at our institution, but chemotherapy at an outside hospital; details of his chemotherapy were not available for this analysis. 14 of the 20 (70%) of the analyzable participants experienced no episode of CIT; 4 subjects experienced a single chemotherapy dose delay due CIT. No patient experienced multiple delays in chemotherapy due to CIT. Two patients required a chemotherapy dose reduction.The mean monthly platelet counts remained controlled throughout the period of analysis. (Figure 1A). The mean romiplostim doses were in the range of 3-5 mcg/kg through 35 months. There were insufficient participants beyond month 36 to allow meaningful interpretation of platelet counts or mean romiplostim doses. There was no evidence of adverse impact on absolute neutrophil count or hemoglobin levels (Figure 1B). No patient developed leukoerythroblastic changes indicative of marrow fibrosis, and no cases of secondary hematologic malignancy were identified. Two participants experienced thrombosis. One individual experienced a deep vein thrombosis. A second participant with an established history of congenital thrombophilia, experienced multiple tumor associated infarctions. The thrombotic events did not lead to discontinuation of participation in the trial for either participant. Of the 44 patients in the phase 2 study who resumed chemotherapy, 21 were alive at 12 months (48%) and 12 were alive at 24 months (27%).Conclusions: In this long-term analysis, romiplostim was effective and safe in the treatment of CIT with no evidence of drug resistance, marrow fibrosis, or secondary hematologic malignancy. The rates of thrombosis were no higher than expected for this patient demographic. There are some limitations to our analysis which includes our inability to accurately capture non-parenteral chemotherapy (oral or investigational agents) which were excluded from our analysis. We are unable to assess an impact on overall survival or cancer progression. However, the fact that half the participants were alive at 12 months and a quarter at 24 months is a reassuring signal. The analysis also is limited to the patients who were eligible for the initial phase 2 trial and corrected their platelet count within 3 weeks. Within these limitations, the extension study provides reassurance for long-term efficacy and safety of romiplostim treatment for CIT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare. OffLabel Disclosure:Romiplostim is approved to increase platelet counts in ITP and pre-surgery. We are describing the results of a clinical trial.

Thrombopoietin Level Predicts Response to Treatment with Romiplostim in Chemotherapy-Induced Thrombocytopenia

INTRODUCTION:Chemotherapy-induced thrombocytopenia (CIT) is a common complication of cancer therapy. Due to the lack of FDA-approved therapies for CIT and clear limitations of platelet transfusions, clinicians often must choose between reducing dose intensity, delaying treatment, switching to an alternative regimen less prone to thrombocytopenia, or even discontinuing therapy altogether. Lower overall survival in CIT is associated with bleeding complications in patients proceeding with chemotherapy as well as patients managed with reductions in relative dose intensity of chemotherapy due to dose reduction and/or treatment delay. Although there are no current FDA-approved therapies for CIT, evidence has emerged supporting use of romiplostim to treat CIT. However, predicting clinical response to romiplostim before initiation is not currently possible due to the lack of a known predictive biomarker. Baseline endogenous TPO levels may, however, be a predictive biomarker for response to thrombopoietin receptor agonists. Prior studies have demonstrated the utility of baseline TPO level to predict romiplostim response in ITP and avatrombopag response in thrombocytopenia of chronic liver disease. Because measurement of TPO level prior to romiplostim treatment of CIT is standard at our institution, we investigated the utility of baseline TPO level to predict romiplostim response in CIT.METHODS:We performed an observational study of patients age ≥18 years who had TPO levels measured and received romiplostim for the treatment of CIT. For each weekly on-romiplostim platelet (Plt) count assessment, clinical response was defined as Plt ≥75×10 9/L and ≥30×10 9/L above pretreatment baseline. Overall, moderate, and superior classes of treatment response were defined based on response fraction (RF) of weekly Plt assessments meeting clinical response criteria (RF >0, ≥ 0.6, and ≥ 0.8, respectively). Median TPO levels were compared in those patients with and without a moderate response or a superior response using the Mann-Whitney U test. A generalized linear model was used to model the logit transformation of RF to predict response fraction based on TPO level. Receiver operating characteristic (ROC) analysis was performed to identify TPO level thresholds for optimal discrimination of those who achieved moderate and superior responses from those who did not.RESULTS:Patients: 63 patients met inclusion criteria. Baseline patient characteristics are detailed in TABLE 1.Relation of TPO Level and Romiplostim Response: Median (IQR) TPO level was lower in patients who achieved a moderate response to romiplostim versus those who did not, 234 (135-1085) pg/mL versus 665 (244-1970) pg/mL (P=0.034) and lower still in patients who achieved a superior response versus those who did not, 212 (91-690) pg/mL versus 559 (173-1851) pg/mL (P=0.023) (FIGURE 1). A generalized linear model demonstrated a significantly higher predicted response fraction as TPO level declined (P=0.036, Figure 2). TPO level was significantly correlated with lowest effective romiplostim dose (r=0.27, P=0.049).Optimal TPO Thresholds for Predicting Response: Utilizing Youden's index, the optimally discriminant TPO level threshold for moderate response to romiplostim was ≤457 pg/mL, which predicted a 61% probability of response in those with a TPO level ≤457 pg/mL and a 65% probability of non-response in those with a TPO level >457 pg/mL (Figure 3A). The optimally discriminant TPO level threshold for superior response to romiplostim was ≤260 pg/mL, which predicted a 59% probability of response in those with a TPO level ≤260 pg/mL and a 70% probability of non-response in those with a TPO level >260 pg/mL (Figure 3B). A near trivial response rate was associated with extreme TPO elevations (e.g., 7% for TPO level >1978 pg/mL, Figure 3).CONCLUSION:Lower TPO levels predict for a higher likelihood and depth of response to romiplostim in CIT, extreme TPO elevations predict strongly for non-response, and higher doses of romiplostim may be needed in patients with moderate TPO elevations to achieve a response. Considering the significant impact of CIT on patient outcomes as a result of treatment delays and dose reductions, baseline serum TPO level in patients with CIT may be a clinically useful biomarker in predicting response to romiplostim, and therefore potentially useful in guiding patient selection and dosing. [Display omitted] DisclosuresKuter: Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, BioCryst, Bristol Myers Squibb (BMS), Caremark, CRICO, Daiichi Sankyo, Dova, Genzyme, Immunovant, Incyte, Kyowa-Kirin, Merck Sharp Dohme, Momenta, Novartis, Pfizer, Principia, Protalex, Protalix, Rigel: Consultancy, Other: grant support and consulting fees; Up-to-Date: Patents & Royalties: Up-To-Date; Rubius: Current equity holder in publicly-traded company; Platelet Disorder Support Association: Membership on an entity's Board of Directors or advisory committees; Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, Bristol Myers Squibb (BMS), Immunovant, Kezar, Principia, Protalex, Rigel, Takeda (Bioverativ), UCB: Research Funding. Al-Samkari: Novartis: Consultancy; Rigel: Consultancy; Moderna: Consultancy; Argenx: Consultancy; Amgen: Research Funding; Dova/Sobi: Consultancy, Research Funding; Agios: Consultancy, Research Funding. OffLabel Disclosure:Romiplostim is a thrombopoietin-receptor agonist (TPO-RA) used off-label for chemotherapy-induced thrombocytopenia. TPO-RAs are well-established in the treatment of numerous etiologies of thrombocytopenia, including immune thrombocytopenia (ITP), aplastic anemia, and thrombocytopenia of chronic liver disease.

1693P Efficacy of corticosteroids in the treatment of chemotherapy-induced thrombocytopenia

Chemotherapy-induced thrombocytopenia (CIT, platelet [PLT] count ≤ 100,000/μL after chemotherapy) is a common side effect with an incidence ranging from 16.5% to 21.8% in the global population, but higher than 30% in the patients treated with platinum- or gemcitabine-based regimens. Its treatment is an unmet need and several agents have been studied with unsatisfactory results. Corticosteroids (CSs) are commonly used, even if low evidence is available. The present study aims to observe whether CSs have a positive impact on the outcome of CIT.

Efficacy and Thrombotic Adverse Events of Romiplostim Use in Patients with Thrombocytopenia Related to Underlying Malignancies

Background: Chemotherapy-Induced Thrombocytopenia (CIT) often results in treatment delay, dose reduction, or need for alternate cancer therapy. There is no validated or approved treatment of CIT. At our institution, the thrombopoietin-receptor agonist romiplostim, is being tested in a phase II clinical trial to treat CIT (being reported separately). Further, since there is no alternative, some oncologists have been using romiplostim off-label/off study to treat CIT and prevent recurrence of CIT when chemotherapy is resumed. Raising the platelet count could potentially increase the risk of thrombosis. Therefore, as a Quality Assessment initiative, we conducted a retrospective analysis of all use of romiplostim in cancer patients at MSKCC to determine the efficacy for treatment of CIT, as well as rates of thrombosis.Methods: We performed a retrospective review of all romiplostim use in cancer patients at MSKCC from 1/1/2010 to 4/14/2017. Patients without cancer or patients whose thrombocytopenia was due to an unrelated indication, such as ITP, Evans syndrome, underlying cirrhosis, or hereditary thrombocytopenia syndromes, were not included in this analysis. All medical records, radiology reports, and romiplostim administration records were reviewed by one or more study investigator. The study was approved by the IRB.Results: From 1/1/2010 through 4/14/2017, romiplostim use was documented in 292 patients. We derived 239 patients with cancer-associated indications. 185 (77.4%) of patients had thrombocytopenia related to chemotherapy and/or radiation therapy. Other causes of thrombocytopenia included primary or metastatic cancer of the liver (n=21, 8.8%), bone metastases (n=16, 6.7%), immune thrombocytopenia related to lymphoma (n=11, 4.6%), or other (n=6, 2.5%). 184 patients had solid tumors (77%) and 55 had hematologic malignancy (23%).We performed an analysis of efficacy response to romiplostim in the cohort of solid tumor patients and lymphoid malignancies (lymphoma/myeloma), the two groups with the most patients (Table 1A). The analysis of lymphoma/myeloma below does not include stem cell transplant patients. One solid tumor patient died before any followup labs were available and is not included in the analysis.For both solid tumor and lymphoid malignancies, the mean platelet counts at least doubled by day 14. Resumption of chemotherapy was at the discretion of the treating oncologist, and beyond Day 14 the platelet counts reflected the competing effects of maintenance romiplostim support of the platelet counts and platelet suppression by chemotherapy. The majority of patients tolerated resumption of chemotherapy without reoccurrence of CIT (Data not shown).We analyzed the rates of thrombosis, adjusted for time of exposure to romiplostim (Table 1B). The cumulative romiplostim use in the 239 patients was 129 years. There were a total of 15 venous thromboembolic events (DVT and/or PE). This calculated to 11.6% VTE events per patient-year, well within the historical rate of thrombosis in patients with metastatic cancer or lymphoma on chemotherapy (i.e. Khorana AA et al, Cancer 2013;119:648-55). In addition, no episodes of ischemic stroke or myocardial infarction were identified in the cancer patients while on romiplostim.Discussion: In this retrospective analysis of romiplostim use in cancer patients, we found evidence of efficacy in patients with solid tumors and lymphoid malignancies. Platelet counts increased over two-fold within 14 days of initiation of romiplostim. And importantly, we did not find evidence of increased thrombotic rates compared with historical experience. How to optimally utilize romiplostim in cancer patients with thrombocytopenia is the focus of ongoing clinical research. [Display omitted] DisclosuresSoff:Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding.

Romiplostim for Chemotherapy-Induced Thrombocytopenia (CIT). Results of a Phase 2 Trial

Background:CIT is a common complication of chemotherapy, resulting in delay or dose reduction of treatment. There is no approved or validated treatment. We report the first prospective trial showing correction and prevention of recurrence of CIT.Methods: A phase II, open label trial of romiplostim, a thrombopoietin receptor agonist, versus observation control. Solid tumor patients with at least 4 weeks of thrombocytopenia (<100,000/mcL), despite reduction or delay in chemotherapy were randomized, 2:1 to weekly romiplostim versus observation. Primary endpoint was correction of platelet count to >100,000/mcL within 3 weeks. Secondary endpoints included safety and resumption of chemotherapy without recurrence of CIT. Observation patients who failed to correct their platelet counts, were eligible to cross-over to receive romiplostim (not shown). Analysis was by Intention-To-Treat, and statistics were by two-tailed Fisher's exact test.Results: 40 patients were enrolled. Mean age was 58 years (range 28-77). All patients had either metastatic disease (35), or locally advanced disease (5). The majority had GI cancer (22). When 8 observation patients were enrolled and reached primary endpoint, an unplanned interim analysis revealed significant benefit of romiplostim (Table, P = <0.001). The observation arm was discontinued out of consideration for trial beneficence, and the trial continued accrual as a single arm study of romiplostim.Of the 32 patients who received romiplostim upfront, 27 (84%) corrected their platelet counts within 3 weeks. Of the 5 failures, 2 patients were protocol violations because their chemotherapy was prematurely resumed prior to platelet correction. The mean effective romiplostim dose for platelet count correction was 2.5 mcg/kg (range 1.8-4.1). 25 patients resumed chemotherapy after correction of their CIT and weekly romiplostim was titrated for target platelet count of 150,000mcL. Only one patient had recurrence of CIT.We saw no evidence of adverse effects on the bone marrow. Four (12.5%) of the 32 romiplostim patients experienced a thrombosis. One had a symptomatic PE, one had an incidentally identified PE and two patients had calf DVTs. These patients were all at high risk of thrombosis, with metastatic or locally advanced pancreas (2), colorectal, and hepatocellular carcinoma.Only three patients in the romiplostim cohort required platelet transfusion. One had an upper GI bleed from a gastric tear, and two patients received platelet transfusion during terminal hospitalizations for progression of disease.Discussion: We demonstrate that romiplostim can effectively reverse CIT in solid tumor patients, allowing for resumption and maintenance of cancer-directed therapy in the large majority of patients. Based on prior literature, a thrombosis rate of 12.5% in patients with metastatic GI cancers, on chemotherapy, is within the expected range. Further study is needed to determine in which settings effective treatment of CIT will lead to meaningful clinical benefit. [Display omitted] DisclosuresSoff:Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding.

High-intensity focused ultrasound ablation for treatment of chemotherapy-induced thrombocytopenia and hypersplenism.

3082 Background: Chemotherapy-induced thrombocytopenia (CIT) contributes to treatment dose delay and/or modification, often resulting in poorer survival and disease progression. Compared with partial splenic embolization (PSE) and drugs, high-intensity focused ultrasound has the advantages as following: (1) it is a noninvasive treatment modality with potentially fewer adverse effects and complications; (2) the hospital stay and recovery time after treatment are short; (3) its cost is relatively low compared to surgery. The purpose of this work was to preliminarily investigate the efficacy and safety of high intensity focused ultrasound treatment of chemotherapy-induced thrombocytopenia (CIT) and hypersplenism. Methods: 26 patients with chemotherapy-induced thrombocytopenia and hypersplenism (15 male and 11 female; median age, 56 years; range, 51-66 years) were treated with ultrasound guided high-intensity focused ultrasound. Complications were recorded. Laboratory examination and magnetic resonance imaging were used to evaluate the efficacy. The spleen volume and ablation volume rate of the spleen were calculated by MRI after treatment. They were followed closely for at least 6 months. Results: After high-intensity focused ultrasound treatment, the MRI showed that the ablation area had turned into a non-perfused volume, the mean percent spleen ablation volume was 18.76% ± 6.1% (range, 11.17%-32.34%). After 6 months of HIFU ablation, the ablated area shrank evidently; the sunken spleen formed a lobulated shape and the splenic volume decreased. The platelet count increased 3-7 days after treatment and remained for 1-2weeks higher than baseline (53.33 ± 15.80 × 109/L). The white blood cell count and platelet count of the patients were substantially improved during the follow-up period. No substantial difference was observed in RBC counts between baseline and after treatment. In addition, symptoms such as epistaxis and gingival bleeding were ameliorated or even eliminated, and the quality of life was improved. Follow-up imaging showed a nonperfused volume in the spleen. Conclusions: For the first time to our knowledge, high-intensity focused ultrasound ablation was used to treat Chemotherapy-induced thrombocytopenia (CIT) and hypersplenism. High-intensity focused ultrasound ablation of the spleen may cause damage to a certain volume of the spleen parenchyma to achieve the purpose of hypersplenism treatment. High intensity focused ultrasound may be an effective and safe alternative for treatment of CIT and hypersplenism.

Randomized, Blinded, Placebo-Controlled Phase I Trial of Pegylated Recombinant Human Megakaryocyte Growth and Development Factor With Filgrastim After Dose-Intensive Chemotherapy in Patients With Advanced Cancer

AbstractThrombocytopenia caused by chemotherapy is an important cause of morbidity and mortality in the treatment of malignant disease. Recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF ) is a potent stimulator of megakaryocytopoiesis and prevents chemotherapy-induced thrombocytopenia in preclinical studies. We administered PEG-rHuMGDF with filgrastim after dose-intensive chemotherapy to 41 patients with advanced cancers to determine its safety and effects on hematologic recovery. Carboplatin 600 mg/m2 and cyclophosphamide 1,200 mg/m2 were administered to patients with advanced cancer. Patients were randomly assigned to receive blinded study drug, either PEG-rHuMGDF or placebo (3-to-1 ratio), commencing the day after chemotherapy. PEG-rHuMGDF was given at doses of 0.03, 0.1, 0.3, 1.0, 3.0, and 5.0 μg per kilogram body weight by daily subcutaneous injection for between 7 and 20 days. All patients received concurrent filgrastim 5 μg per kilogram body weight per day until neutrophil recovery. Fifteen patients had received PEG-rHuMGDF alone in a previous phase I study. Platelet function and peripheral blood progenitor cells (PBPC) were assessed. PEG-rHuMGDF enhanced platelet recovery in a dose-related manner when compared with placebo. The platelet nadir occurred earlier in patients given PEG-rHuMGDF (P = .002) but there was no difference in the depth of the nadir. Recovery to baseline platelet count was achieved significantly earlier following PEG-rHuMGDF administration compared with placebo (median, 17 days for PEG-rHuMGDF 0.3 to 5.0 μg/kg versus 22 days for placebo, P = .014). In addition, platelet recovery was faster in patients who had previously received PEG-rHuMGDF, suggesting that pretreatment might be beneficial. Platelet function did not change during or after administration of PEG-rHuMGDF. Levels of PBPC on day 15 after chemotherapy were significantly greater in patients administered PEG-rHuMGDF 0.3 to 5.0 μg/kg and filgrastim compared with those given placebo plus filgrastim. PEG-rHuMGDF was well tolerated at all doses. Two patients given PEG-rHuMGDF had a thrombotic episode. PEG-rHuMGDF accelerates platelet recovery after moderately dose-intensive carboplatin and cyclophosphamide, and is likely to be clinically useful in treatment of chemotherapy-induced thrombocytopenia. Because it enhances mobilization of PBPC by filgrastim, PEG-rHuMGDF might also allow more efficient collection of stem cells for autologous or allogeneic transplantation.

Eltrombopag inhibits the proliferation of Ewing sarcoma cells via iron chelation and impaired DNA replication

BackgroundThe treatment of Ewing sarcoma, an aggressive bone and soft tissue sarcoma, is associated with suboptimal outcomes and significant side-effects. Consequently, there is an urgent need to identify novel therapies that will improve outcomes for children and adults with Ewing sarcoma tumors while also decreasing treatment-related toxicities.MethodsWe analyzed data from the PRISM drug repurposing screen, which tested the activity of 4518 drugs across 578 cancer cell lines, to identify drugs that selectively inhibit the growth of Ewing sarcoma cell lines. We then tested the effects of a top hit from the screen on cell proliferation, cell cycle progression, and activation of the DNA damage pathway using Ewing sarcoma cell lines. We also used a CRISPR/Cas9 gene knockout approach to investigate the role of Schlafen 11 (SLFN11), a restriction factor for DNA replication stress that is overexpressed in Ewing sarcoma tumors, in mediating the sensitivity of Ewing sarcoma cells to the drug.ResultsWe found that eltrombopag, an FDA-approved thrombopoietin-receptor agonist (TPO-RA) that is currently being evaluated as a treatment for chemotherapy-induced thrombocytopenia, inhibits the growth of Ewing sarcoma cell lines in vitro in proliferation and colony formation assays. However, from a mechanistic standpoint, the thrombopoietin receptor is not expressed in Ewing sarcoma cells and we show that eltrombopag impairs DNA replication and causes DNA damage in Ewing sarcoma cells by chelating iron, a known “off-target” effect of the drug. We also found that the sensitivity of Ewing sarcoma cells to eltrombopag is mediated, in part, by SLFN11, which regulates the cellular response to DNA replication stress.ConclusionsEwing sarcoma cell lines are sensitive to eltrombopag and this drug could improve outcomes for patients with Ewing sarcoma tumors by both targeting the tumor, via chelation of iron and inhibition of DNA replication, and reducing chemotherapy-induced thrombocytopenia, via stimulation of the thrombopoietin receptor.