Photo courtesy of GSK
Eltrombopag (Promacta)
Adding eltrombopag to immunosuppressive therapy (IST) can produce high rates of response in treatment-naïve severe aplastic anemia (SAA), according to research published in NEJM.
In patients who received eltrombopag for 6 months, the overall response rate (ORR) was 94%, and the complete response (CR) rate was 58%.
Researchers noted that these rates are “markedly higher” than response rates observed in historical controls who received IST alone.
The team also said the safety profile of eltrombopag in this study was consistent with the known safety profile of the drug.
“[E]ltrombopag plus standard immunosuppressive therapy appeared to increase the overall response rate and substantially increase the frequency, speed, and robustness of hematologic recovery in patients with SAA compared to historical controls,” said study author Danielle Townsley, MD, of the National Heart, Lung and Blood Institute (NHLBI).
She and her colleagues at NHLBI conducted this research through a Cooperative Research and Development Agreement with Novartis, the company that markets eltrombopag as Promacta/Revolade.
Patients and treatment
This phase 1/2 trial included 92 patients with treatment-naïve SAA. The patients’ median age was 32 (range, 3-82), and 54% of them were male.
At baseline, the patients’ median neutrophil count was 310/mm3 (range, 0-1810), their median reticulocyte count was 19,950/mm3 (range, 1600-60,400), and their median platelet count was 9000/mm3 (range, 0-37,000). Their median thrombopoietin level was 3163 pg/ml (range, 1806-4955).
All patients received horse antithymocyte globulin on days 1 to 4 and cyclosporine from day 1 to 6 months. The patients also received eltrombopag at an age-dependent dose.
They received eltrombopag at 150 mg daily if they were 12 years or older, 75 mg daily if they were 6 to 11, and 2.5 mg/kg/day if they were 2 to 5 years of age.
Patients were also split into 3 cohorts according to treatment duration:
- Cohort 1 received eltrombopag from day 14 to the 6-month mark.
- Cohort 2 received eltrombopag from day 14 to the 3-month mark.
- Cohort 3 received eltrombopag from day 1 to 6 months.
Response
The study’s primary efficacy endpoint was hematologic CR at 6 months. CR was defined as an absolute neutrophil count of at least 1000/mm3, a hemoglobin level of at least 10 g/dL, and a platelet count of at least 100,000/mm3.
Secondary endpoints included partial response (PR) and ORR, among other endpoints. ORR was the rate of CR plus PR. Patients had a PR if they had blood counts that no longer met the criteria for SAA but they did not meet criteria for CR.
For all cohorts, at 6 months, the ORR was 87%, and the CR rate was 39%.
In cohort 1, the ORR was 80%, and the CR rate was 33%.
In cohort 2, the ORR was 87%, and the CR rate was 26%.
In cohort 3, the ORR was 94%, and the CR rate was 58%.
The researchers noted that ORRs were higher across all cohorts than the ORR observed in a historical cohort (66%). The cohort consisted of 102 patients who had received standard IST while serving as controls in 1 of 2 recent NHLBI clinical trials.
Relapse
Thirty-two percent of responding patients (25/78) relapsed after 6 months.
After the study protocol was amended to allow the continuation of low-dose cyclosporine from 6 months to 2 years, the frequency of relapse decreased.
Fourteen percent of responders receiving low-dose cyclosporine beyond 6 months relapsed (6/43), compared to 54% of patients who stopped cyclosporine at 6 months (19/35).
Restarting full-dose cyclosporine reversed relapse and increased blood counts in 13 of 25 patients. Adding eltrombopag reversed relapse in an additional 10 patients.
Survival
The 2-year overall survival rate was 97% for the entire study population and 99% when data were censored for transplant.
Twelve patients under went transplant after eltrombopag. Six of them had not responded or were still transfusion-dependent, 3 relapsed, and 3 had clonal evolution.
Three patients died—1 while on study and 2 after transplant.
Clonal evolution and PNH
The researchers said the frequency of clonal evolution in this study was similar to that observed in the historical cohort of patients who received standard IST. The rate of clonal evolution at 2 years was 8% in both groups.
In the current study, 7 patients had clonal evolution at 2 years. Five patients had loss of chromosome 7, which was associated with dysplastic bone marrow changes in 3 patients.
One patient with a complex karyotype progressed to acute myeloid leukemia.
Two patients developed hemolytic paroxysmal nocturnal hemoglobinuria (PNH).
Safety
Two severe adverse events (AEs) were attributed to eltrombopag. Both were cutaneous eruptions—a grade 2 and a grade 3 event. Both AEs led to discontinuation of the drug.
Seven patients briefly stopped taking eltrombopag during the first 2 weeks of treatment due to transient elevations in liver enzymes.
AEs not attributed to eltrombopag were neutropenic infections and AEs known to be associated with IST.
The single patient who died on study was a non-responder who died 3 months after starting treatment. The death was due to paraneoplastic encephalopathy, which was attributed to thymoma that predated study entry.
