A single center experience with romiplostim for the management of chemotherapy‐induced thrombocytopenia

Thrombocytopenia is a frequent complication among cancer patients receiving chemotherapy for which there are limited treatment options. Management is typically limited to platelet transfusions or chemotherapy dose reductions and delays. Romiplostim is a thrombopoietin receptor agonist that mimics the action of endogenous thrombopoietin, resulting in increased platelet production. Romiplostim is approved for the treatment of chronic idiopathic thrombocytopenic purpura, however there is limited data to support its use in chemotherapy-induced thrombocytopenia (CIT). Our retrospective case series represents the largest cohort to date of romiplostim use in the CIT population and describes our experience managing 42 solid-tumor cancer patients who received romiplostim for the management of CIT at a single center from August 2014 to January 2017. This study was approved by the Institutional Review Board of Dana Farber Cancer Institute and included all adult patients with a diagnosis of solid tumor malignancy who received romiplostim concurrently with chemotherapy. Baseline characteristics were collected including age, cancer type and stage, chemotherapy, baseline platelet counts, and comorbidities associated with thrombocytopenia. Romiplostim dosing and efficacy were assessed in all patients receiving more than one dose. Efficacy assessments included acheivement of platelets >100 × 109/L, continuation of at least two additional cycles of chemotherapy, and duration of treatment. All patients receiving at least one dose of romiplostim were assessed for safety. These patients were reviewed for any cases of thrombosis or other adverse events attributed to romiplostim. In this descriptive analysis, we report on our patient outcomes with the use of romiplostim for CIT. Population: We identified 42 patients who received romiplostim concurrently with chemotherapy (Table 1). Patients encompassed a wide variety of malignancies with the most common being gastrointestinal cancers. The majority of patients had stage IV metastatic cancer upon diagnosis. Dosing: Thirty-seven patients received more than one dose of romiplostim and were evaluated for dosing and efficacy. Romiplostim was dosed at the clinician's discretion and administration on the same day as chemotherapy was avoided. In general, romiplostim was administered 1–2 times between chemotherapy cycles with a median time between doses of 2 weeks (Supporting Information Table I). The median starting dose was 2 mcg/kg and most patients achieved platelets >100 × 109/L following one dose of romiplostim. Efficacy: Thirt-five out of 37 patients achieved platelet counts >100 × 109/L and 34 patients received at least two additional cycles of chemotherapy (Supporting Information Table II). The median duration of treatment was 18 weeks and patients were able to continue with a median of five cycles of chemotherapy while receiving romiplostim. Romiplostim was discontinued for a variety of reasons with the most common being death and change in chemotherapy. About 24.3% of patients continued romiplostim for over 15 doses. These patients were able to continue chemotherapy without dose-limiting thrombocytopenia for an average of 15.6 cycles (Supporting Information Figure 1). Safety: Six out of the 42 patients identified in our study developed thrombosis during or shortly following romiplostim therapy (Supporting Information Table III). Five out of six events occurred in patients with pancreatic cancer. One deep vein thrombosis occurred in a patient with astrocytoma. There was no association observed between platelet count and thrombosis or between romiplostim dose and thrombosis. There were no deaths caused by thrombosis. One patient was diagnosed with acute myelogenous leukemia after receiving one dose of romiplostim. Next-generation sequencing revealed mutations in NRAS and TET2. In the solid-tumor population, CIT is typically observed as a cumulative toxicity following the receipt of multiple cycles of chemotherapy and is managed with chemotherapy dose reductions and delays.1 Romiplostim offers an alternative to the treatment of CIT. Data to support the use of romiplostim for CIT is currently limited to abstracts and one retrospective case series by Parameswaran et al. describes 20 patients with CIT.1-4 In that study, platelet counts improved in all patients and increased to ≥100 × 109/L in 19 out of 20 patients. Our retrospective study represents the largest case series to date of patients receiving romiplostim for the management of CIT and corroborates the positive findings of Parameswaran et al. However, in our study romiplostim was primarily dosed intra-cycle rather than on a weekly basis. Romiplostim begins to increase platelet counts 4–9 days after administration, with its effect peaking at 12–16 days.5 Depending on the length of the cyle, 1–2 doses per cycle was sufficient to maintain a platelet count ≥100 × 109/L at the time of the next chemotherapy cycle. In terms of safety, we observed six thromboembolic events out of the 42 patients assessed for safety for an overall thrombotic rate of 14.3% (3.7–24.9%, 95% CI). These results were similar to that of Parameswaran et al. who reported three thrombotic events in the 20 patients in a similar solid tumor population. The overall incidence of thrombosis in the oncology population is difficult to characterize with reported rates ranging greatly from 3.8% to 30.7%.6 Considering the majority of our patients possessed many risk factors for thrombosis including advanced cancer stage (88%), active chemotherapy (100%), and high-risk cancer types (28%), we believe our thrombosis rate is consistent with that expected for our population. Interestingly, five out of six thrombotic events occurred in pancreatic cancer patients, a disease that is associated with a particularly high rate of thrombosis. Given these findings, one may consider using concurrent thromboprophylaxis or avoiding romiplostim in high-risk patients. Though our study suggests that romiplostim may be effective in the mangement of CIT, the retrospective nature of this study and our lack of a standardized practice is limiting. Prospective trials are necessary to evaluate its role in clinical practice and determine whether additional chemotherapy in the setting of romiplostim administration will improve overall survival, quality of life measures, and cost-effectiveness. Future prosective trials should also be designed to identify the optimal dose and schedule of romiplostim for CIT and assess for safety and minimization of potential adverse events. Nothing to report. Additional Supporting Information may be found online in the supporting information tab for this article. Supporting Information Figure 1 Supporting Information Table 1 Supporting Information Table 2 Supporting Information Table 3 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.