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Multicenter study of romiplostim for CIT
improvement that is often impractical or impossible to continue for extended periods. Therefore, chemotherapy dose reductions and treatment delays are the current stan- dard of care for the management of CIT, allowing platelet count to recover to the desired count for subsequent administration of cancer-directed treatment. Reduced rel- ative dose intensity (RDI) that results from CIT-related treatment delays and dose reductions may reduce progres- sion-free survival (PFS) and overall survival (OS).3,4 Conversely, management or prevention of CIT with thrombopoietic agents may maintain RDI and improve OS, particularly in curable malignancies.5-8 Bleeding in CIT has major consequences for patient outcomes; patients with CIT who develop major bleeding have been shown to have substantially lower OS.4
Thrombopoietin receptor agonists (TPO-RA) have been developed and approved for use in immune thrombocytopenia (ITP),9 aplastic anemia,10 hepatitis C-associated thrombocytopenia,11 and perioperative thrombocytopenia.12-14 Romiplostim is a weekly subcuta- neously-administered TPO-RA currently approved to treat ITP. Maximal doses of romiplostim are considerably more potent in raising the platelet count than the oral small molecule TPO-RA in healthy subjects and possibly in ITP,15-17 making this an ideal agent for investigation into myelosuppressive thrombocytopenias such as CIT. To date, studies of romiplostim to manage CIT have been limited to case series and small single-center studies.18-21 These studies suggest that romiplostim is effective in rais- ing the platelet count in patients with solid tumors. Predictors of romiplostim non-response, optimal dosing regimens, and use in non-myeloid hematologic malignan- cies (lymphoma and myeloma) have not been evaluated. Clinical outcomes data more relevant than simple platelet count measurements, such as resumption of treatment without further chemotherapy dose reductions or treat- ment delays, bleeding, or thrombosis, are limited. The safety of TPO-RA in cancer patients is a concern, as TPO- RA carry an associated risk for venous thromboembolism (VTE), which could add to the baseline risk associated with malignancy.
The present study aims to address these questions and evaluate romiplostim to manage CIT in a large cohort of both solid tumor and hematologic malignancy patients treated at four affiliated US academic cancer centers. Institutional pathways guided administration of romi- plostim at each center. Management of CIT remains an off-label use of romiplostim.
Methods
Patients and data collection
This study was approved by the Institutional Review Board of Partners Healthcare (approval PHS/2015000152). All patients aged ≥18 years with thrombocytopenia treated with romiplostim to support administration of chemotherapy to treat solid tumors or non-myeloid hematologic malignancies (multiple myeloma, Hodgkin lymphoma or aggressive non-Hodgkin lymphoma) between July 1st 2009 and July 1st 2019 at the four participating institutions (Massachusetts General Hospital, Brigham and Women’s Hospital, Dana-Farber Cancer Institute, and Newton- Wellesley Hospital) were identified using the Research Patient Data Registry at Partners Healthcare. The specific patient data col- lected are available in the Online Supplementary Methods.
Institutional romiplostim chemotherapy-induced thrombocytopenia pathways: weekly versus intracycle dosing
Patients qualified to enter their institutional romiplostim CIT pathway after persistent thrombocytopenia (platelet count <100x109/L) at least 3 weeks from the date of last chemotherapy administration or after a delay in chemotherapy regimen initia- tion ≥1 week due to thrombocytopenia. For solid tumor patients, two institutions utilized a weekly romiplostim CIT pathway in which romiplostim was administered weekly irre- spective of timing of chemotherapy administration and two uti- lized an intracycle romiplostim CIT pathway in which romi- plostim was administered primarily on chemotherapy off- weeks, on average twice per month (see Figure 1 for dosing pathways). Regardless of pathway, platelet counts were obtained weekly. All hematologic malignancy patients were treated at institutions that employed the weekly romiplostim treatment pathway.
Effectiveness and safety measures
The primary outcome was achievement of a romiplostim response, defined as a median on-romiplostim platelet count ≥75x109/L and at least 30x109/L higher than the pretreatment baseline. Median on-romiplostim platelet counts were used in all analyses comparing individual patient baseline platelet count to individual patient on-romiplostim platelet count. As romiplostim response is a measure of effectiveness over the entire duration of romiplostim treatment, the time from romiplostim initiation to first achievement of platelet count ≥100x109/L was also evaluated. Because there is no universally accepted platelet count threshold that defines CIT recurrence, incidence rates of all measured platelet counts below thresholds of 50x109/L, 75x109/L, and 100x109/L were also evaluated. Similarly, thrombocytosis was defined as >400x109/L and incidence rates were evaluated.
Other clinical outcomes included rates of chemotherapy intensity reduction (dose reduction or treatment delay) specifi- cally for thrombocytopenia and rates of platelet transfusion, bleeding, and arterial or venous thromboembolic events.
Patients treated with romiplostim for CIT but not able to resume chemotherapy were included in analyses of bleeding, VTE, and platelet count outcomes while on romiplostim treat- ment but not analyses of chemotherapy intensity reduction or platelet transfusion.
Predictors of romiplostim non-response
Predictors of failure to achieve a romiplostim response (referred to hereafter as “predictors of romiplostim non- response”) were evaluated using a multivariable logistic model (see Online Supplementary Methods for development of the model).
Statistical analysis
Median individual patient platelet counts on romiplostim sup- port were compared with the pre-romiplostim baseline platelet count with the Wilcoxon signed-rank test. Predictors of romi- plostim non-response were identified using a multivariable logistic model (see Online Supplementary Methods).
Solid tumor patients receiving weekly versus intracycle dosing were compared. Rates of thrombosis, bleeding, chemotherapy delay/dose reduction, platelet transfusion, and platelet counts <50x109/L, <75x109/L, <100x109/L, and >400x109/L were com- pared in the two groups with negative binomial regression mod- els (see Online Supplementary Methods). Baseline and median on- romiplostim platelet counts for each group were compared with the Mann-Whitney U test.
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