Efficacy and Safety of Extended Use of Romiplostim Treatment for Chemotherapy-Induced Thrombocytopenia
Authors: Wilkins Cy R , Ortiz Jocelyn , Gilbert Leah , Yin Shen , Mones Jodi V. , Parameswaran Rekha , Mantha Simon , Soff Gerald A. 
Published: November 2021

Abstract
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.
Figure 1 Figure 1.

Disclosures
No 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.