ORLANDO, Fla. — Eltrombopag improved platelet counts and alleviated fatigue among low-risk patients with myelodysplastic syndromes who experienced severe thrombocytopenia, according to results of a phase 2 placebo-controlled study presented at the ASH Annual Meeting and Exposition.
Eltrombopag (Promacta, Novartis) — an oral agonist of the thrombopoietin receptor — also appeared well tolerated and did not appear significantly associated with the progression of myelodysplastic syndromes, according to study findings.
Approximately 10% of patients with low-risk myelodysplastic syndromes (MDS) experience severe thrombocytopenia. Researchers seek novel treatments in this setting due to bleeding risk and the scarce efficacy of platelet transfusions.
Esther Natalie Oliva, MD, hematologist in the hematology unit of Azienda Ospedaliera Bianchi-Melacrino-Morelli in Reggio Calabria, Italy, and colleagues sought to evaluate the safety and efficacy of eltrombopag to increase platelet counts in 70 patients with low- or intermediate-1 risk MDS with severe thrombocytopenia. They also sought to evaluate the agent’s impact on patients’ quality of life, platelet transfusion requirements, the incidence and severity of bleeding, and survival.
“Eltrombopag has anti-proliferative effects on leukemic cells and it has shown alone that it inhibits proliferation in many autocrine motility factor cell lines and inhibits the proliferation of leukemia cells from the reduction of intracellular iron and induction of differentiation,” Oliva said during the presentation. “It also inhibits other types of cell lines, so we were confident we could try this drug in this setting.”
By the time of the current interim analysis, researchers had randomly assigned (2:1) 46 patients to the eltrombopag arm and 24 to the control arm.
At the time of analysis, 35 patients had completed at least 24 weeks of the study protocol.
Thirteen of 24 patients (54%) in the eltrombopag group achieved a platelet response compared with three of 11 (27%) patients on the placebo arm. The median time to platelet response was 14 days (interquartile range [IQR], 8-39 days) in the eltrombopag arm and 85 days (IQR, 41-193) in the placebo arm (P = .023).
At 8 weeks, median platelet counts increased from 18 Gi/L (IQR, 10-25) to 44 Gi/L (IQR, 18-70) in the eltrombopag arm, whereas there was no significant change in the placebo arm.
Additional data indicate that at 24 weeks, four patients on the eltrombopag arm achieved an erythroid response compared with no patients assigned placebo. One patient in each arm achieved a neutrophil response.
Complete remissions — or the normalization of bone marrow morphology — occurred in two patients assigned eltrombopag at 3 months, as well as in four additional patients at 6 months.
Researchers measured six aspects of quality of life using the QOL-E scale. Patients in the eltrombopag arm experienced significant improvements in fatigue (P = .014) and MDS-specific symptoms (P = .005), especially among responders.
Nine patients (19%) in the eltrombopag arm experienced grade 3 to grade 4 adverse events related to therapy. The most common therapy-related events included nausea and/or vomiting (n = 6) and hypertransaminasemia (n = 3). Singular instances of hyperbilirubinemia, sepsis, pruritis, heart failure and asthenia also occurred.
MDS disease progression occurred in three patients (6%) assigned eltrombopag and one patient (5%) in the control group, which did not represent a statistically significant difference.
Evolution to acute myeloid leukemia also occurred in a similar proportion of patients on each arm (6% vs. 5%).
“We can now say eltrombopag is manageable with a low toxicity profile,” Oliva said. “It seems to raise platelet counts and induces platelet responses in patients and is not associated with progression or acute myeloid leukemia evolution at this stage of the trial.
“It may also be associated with remission and is associated with improvements in quality of life in responsive patients,” Oliva added. – by Anthony SanFilippo
Oliva EN, et al. Abstract 91. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.
Disclosure: Oliva reports consultant/advisory and speakers’ bureau roles with Amgen, Celgene and Novartis. Please see the abstract for a list of all other researchers’ relevant financial disclosures.