Title : Eltrombopag added to combined immunosuppressive therapy IST in children with acquired severe aplastic anemia accelerates hematologic recovery and should be continued in the second course of IST
Abstract:
Eltrombopag (ELTR) added to first-line standard immunosuppressive therapy (IST) has demonstrated efficacy in adult patients with severe aplastic anemia (SAA), but the data in children remains controversial. We extended our randomized prospective multicenter trial comparing efficacy and safety of ELTR combined with IST (horse antithymocyte globulin (hATG) and cyclosporine) vs IST alone in treatment-naïve children with SAA to evaluate early response and long-term outcomes in a larger patient cohort.
PATIENTS AND METHODS
Patients were randomized into ELTR+IST and IST groups in 1:1 ratio. In ELTR+IST group, patients received ELTR from day 1 for at least 4 months. In Part I of our trial, nonresponders at 4 months received the second course of IST with ELTR, if initial course was standard IST, or without ELTR, if initial course was ELTR+IST (crossover treatment). In Part II, all nonresponders received the second course of IST with ELTR. The endpoints for the pooled analysis were 3-month overall response rate (ORR), non-response rate, second-line treatment efficacy, overall (OS) and event-free (EFS) survival, cumulative incidence (CI) of relapse and CI of clonal evolution.
RESULTS
Overall, 200 pediatric patients (98 in Part I; 102 in Part II) aged 2.0-17.7 years from 12 centers were included, with 99 assigned to ELTR+IST and 101 to IST. The ORR at 3 months was significantly higher in ELTR+IST group than in IST group: 56,6% (56/99) vs. 41,6% (42/101), p=0.034; the median time to overall response was 79 vs. 106 days, p=0.026. Complete response rate at 3 months was significantly higher in ELTR+IST group: 16.2% (16/99) vs. 3.9% (4/101),
p=0.004. In Part I, after the crossover, 63% of initial ELTR(-) nonresponders achieved a response compared to 17% of initial ELTR(+) nonresponders (p=0.011). In Part II, the proportion of patients refractory to initial therapy was higher in the IST group than in the ELTR+IST group: 40.4% (21/52) vs. 22.0% (11/50), p=0.045. Median time to the second course of hATG was 146.5 (104-189) days. At 6 months, 54% (15/28) of initial nonresponders achieved a response: 6/8 (75%) in initial ELTR(+) and 9/20 (45%) in the initial ELTR(-) group. In total, 80.8% (80/99) and 77.2% (78/101) patients in initial ELTR+IST and IST groups, respectively, responded to one or two treatment courses (p=0.534).
With median follow-up of 4.5 (0.1-9.0) years, no significant differences in ELTR+IST and IST groups were observed in terms of 5-year OS (94% vs. 93%, p=0.827), 5-year EFS (52% vs. 47%, p =0.150), CI of relapse (24% vs 18%, p=0.456) and Cl of chromosomal abnormalities (7.5% vs 8.4%, p=0.890). No cases of myeloid malignancy developed.
CONCLUSIONS
ELTR added to IST increased hematological response rate at 3 months in treatment-naïve pediatric patients, allowing for early identification of nonresponders and timely initiation of second-line treatment. The second course of IST without ELTR had limited efficacy among patients who received ELTR up-front. Adding ELTR to the second course of IST was equally effective in both initial ELTR(-) and ELTR(+) patients, indicating that ELTR should be continued in recipients of the second IST course. Clinicaltrials.gov #NCT03413306.
