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Multicenter study of romiplostim for CIT
Figure 3. Median weekly platelet counts for solid tumor patients receiving standard weekly romi- plostim dosing (n=65, dark blue) versus intracy- cle romiplostim dosing (n=57, light blue). Patients with predictors of romi- plostim non-response (bone marrow invasion, prior pelvic irradiation, or prior temozolomide) were excluded from this figure to emphasize the difference specifically attributable to dosing regimen. Error bars represent interquartile ranges.
Given our large sample size, we were able to evaluate predictors of romiplostim non-response using multivari- able logistic modeling; we found that BM invasion by tumor, prior pelvic irradiation, and prior exposure to temozolomide predict poor response to romiplostim treat- ment. The latter finding is consistent with the distinct risk of temozolomide resulting in severe marrow toxicity,28 made manifest by prolonged cytopenias or even aplastic anemia. Our findings suggest evaluation of CIT patients at high risk for BM involvement by tumor (such as patients with metastatic breast, prostate, or lung cancer with known bony involvement) with a BM biopsy may be appropriate before considering romiplostim treatment. Similarly, patients previously treated with pelvic irradia- tion or temozolomide may be better served with alterna- tive approaches to CIT management. Studies of other thrombopoietic agents have demonstrated efficacy in treatment of CIT in lymphoma5 and demonstrated BM invasion by tumor as a predictor of romiplostim non- response in solid tumor patients. Given this, in this study, the overall subpar response of non-myeloid hematologic malignancy patients to romiplostim observed is likely sec- ondary to known BM infiltration by malignancy, although many of these patients were not escalated to maximal doses of romiplostim. Additional studies of romiplostim to treat CIT in lymphoma patients without significant BM involvement are needed to better assess its utility in this population.
With 60.7 patient-years at risk of romiplostim treatment in this study, we were able to meaningfully evaluate rates of thromboembolic and bleeding events on romiplostim treatment. Eight patients developed a VTE event on romi- plostim treatment, a rate of 14 VTE events per 100 patient- years. Given that 75% of our patients had metastatic dis- ease (with one-third of those with localized disease hav- ing primary central nervous system malignancies which impart a high VTE risk) and approximately half had tumor types associated with higher VTE risk, this rate is consis- tent with VTE rates of 10-14 events per 100 patient-years described in epidemiologic studies of similar popula- tions.29,30 No patient developing VTE had thrombocytosis
at the time of VTE diagnosis, with platelet counts ranging between 65-307x109/L (Table 2). Solid tumor patients without predictors of romiplostim non-response had an overall bleeding rate of 16 events per 100 patient-years at risk, consistent with rates in the non-anti-coagulated, non- thrombocytopenic metastatic cancer population.31,32 This rate is considerably lower than rates in prior studies of CIT patients not treated with thrombopoietic agents. In a large retrospective study of 609 solid tumor and lym- phoma patients with 1,262 chemotherapy cycles compli- cated by CIT, World Health Organization (WHO) grade 3 or 4 bleeding occurred in 43 (3.4%) of cycles.4 The rate of WHO grade 3 or 4 bleeding in this study was just 11 out of 1,063 cycles supported with romiplostim (1.0%), and many of these bleeds were likely unrelated to thrombocy- topenia (only six occurred at platelet counts <100x109/L and only three occurred at platelet counts <50x109/L) (Table 3). This same retrospective study also found dra- matically higher rates of platelet transfusion and chemotherapy dose reduction and treatment delay than those observed in the present study.4
Our study has several limitations. As a retrospective, observational study, patients were treated with romi- plostim according to institutional pathways that did not mandate strict adherence to treatment parameters. The overall study population was heterogeneous, including a number of different tumor types and chemotherapy regi- mens. As with many retrospective studies, there is the possibility of selection bias as the patient cohort was defined by those patients enrolled on the romiplostim treatment pathway without evaluating those that were not enrolled. The study was not randomized so cannot quantify the impact of romiplostim treatment compared with a placebo or platelet transfusion-only control group. Although this is the largest study of thrombopoietic growth factor treatment of CIT to date, and the first to include patients with non-myeloid hematologic malignan- cy, the number of patients with hematologic malignancy was low.
In conclusion, romiplostim is effective for the manage- ment of CIT in patients with solid tumors, as demonstrat-
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