The phase II EUROPE multicenter trial confirmed that romiplostim is safe and efficacious in a large subset of patients with lower-risk myelodysplastic syndromes (LR-MDS), although it did not validate the predictive value of certain previously proposed baseline biomarkers of response. EUROPE was designed to investigate the predictive value of biomarkers on the clinical efficacy of single agent romiplostim in patients with LR-MDS and thrombocytopenia. Specifically, retrospective analyses had shown that lower baseline endogenous thrombopoietin (TPO) levels and limited platelet transfusion events (PTE) predicted a greater likelihood of subsequent platelet response to romiplostim.
According to study author, Uwe Platzbecker, MD, of Leipzig University Hospital in Germany, it was important to attempt to validate the value of these biomarkers because LR-MDS with thrombocytopenia is “a rare indication with substantial costs for a drug which is still not approved in this indication.”
The study included 77 patients with LR-MDS and a median platelet count of 25/nL. All patients received subcutaneous romiplostim at a starting dose of 750 μg weekly. Patients were assigned into two cohorts based on previous PTE and TPO serum levels: cohort A had TPO <500 ng/L and PTE <6 units/past year and cohort B had TPO >500 ng/L and/or PTE 6 units/past year or more. Results were published in Leukemia.
Less than half of patients (42%) achieved a hematologic improvement in platelets (HI-P). The researchers could not confirm the value of baseline TPO and platelet transfusion history as biomarkers of response. There was no significant difference in HI-P between cohort A compared with cohort B (47% vs. 31%; p=0.295).
The median duration of HI-P was 340 days, which the researchers called “very encouraging.”
Because a prediction model using TPO and PTE could not be validated, Dr. Platzbecker and colleagues developed an alternative response prediction model. They looked at baseline age, gender, disease duration, hemoglobin count, platelet count, neutrophil count, serum TPO level, WHO subtypes, cytogenetic aberration, red blood cell and platelet transfusion dependency, number of cytopenias, number of mutations, peripheral blood or bone marrow blast count, and several mutation statuses.
“We found that patients with an SRSF2 mutation, as well as those who were not anemic, responded significantly better,” Dr. Platzbecker said, noting that this would need confirmation in subsequent trials.
The researchers identified SRSF2 mutation as a significant predictor of response to romiplostim (p=0.016). More responders displayed an SRSF2 mutation as compared with non-responders (41% vs. 16%; p=0.018).
The prediction model that used platelet count, SRSF2 mutation status, and hemoglobin level with a threshold of 11.4 g/dL resulted in an accuracy of 70% for a correct romiplostim response prediction.
Taken together, patients with LR-MDS with thrombocytopenia (platelet count ≤50/nL) had an HI-P rate of 42% after romiplostim. Patients that also have an SRSF2 mutation had an HI-P rate of 65%, and those that also have both an SRSF2 mutation and baseline hemoglobin greater than 11.4 g/dL had an HI-P rate of 100%.
“Although an earlier study had highlighted the potential risk of romiplostim in accelerating development of [acute myeloid leukemia] or an increase of peripheral blood or bone marrow blasts in [patients with MDS], our study confirms recently reported long-term follow-up data from a randomized controlled trial that showed no increased rate of leukemic progression during romiplostim treatment,” the researchers wrote.
Based on these results, Dr. Platzbecker said that clinicians should be reassured that romiplostim is safe and efficacious in LR-MDS and now have biomarkers to help select the most appropriate patients.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Kubasch AS, Giagounidis A, Metzgeroth G, et al. Prospective validation of a biomarker-driven response prediction model to romiplostim in lower-risk myelodysplastic neoplasms – results of the EUROPE trial by EMSCO. Leukemia. 2022;36(10):2519-2527.
