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 1^st, 2016, to December 31^st, 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.

No relevant conflicts of interest to declare.

The use of Romiplostim (and TPO agonists in general) for the treatment of chemotherapy-induced thrombocytopenia is mentioned in the discussion, although this is not the main focus of this abstract, nor is data presented related to this use.