In this issue of Blood Advances, Shimamura et al1 report on a phase 2 clinical trial clinical trial: A type of research study that tests how a drug, medical device, or treatment approach works in people. There are several types of clinical trials. Treatment trials test new treatment options. Diagnostic trials test new ways to diagnose a disease. Screening trials test the best way to detect a… evaluating the addition of eltrombopag eltrombopag: What are the possible side effects of eltrombopag (Promacta)? Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat. Stop using eltrombopag and call your doctor at once if you have: … (EPAG) to traditional immunosuppressive therapy immunosuppressive therapy: Immunosuppressive drug therapy lowers your body's immune response. This prevents your immune system from attacking your bone marrow, allowing bone marrow stem cells to grow, which raises blood counts. For older patients with acquired aplastic anemia, immunosuppressive drug therapy is the… (IST) in pediatric patients with relapsed or refractory refractory: Not responsive to treatment or cure. For example, refractory anemia is a low red blood cell count that doesn't respond to standard treatments. (R/R) or treatment-naive severe aplastic anemia aplastic anemia: (ay-PLASS-tik uh-NEE_mee-uh) A rare and serious condition in which the bone marrow fails to make enough blood cells - red blood cells, white blood cells, and platelets. The term aplastic is a Greek word meaning not to form. Anemia is a condition that happens when red blood cell count is low. Most… (SAA). They found that the pharmacokinetic (PK) profile and safety signal for EPAG were similar to those previously reported, and that in pediatric patients with R/R SAA, IST combined with EPAG demonstrated a trend toward a favorable overall response rate (ORR), although in a small number of patients (n = 14). The response rate in treatment-naive SAA was lower than expected with 48% overall response at 26 weeks.
Standard first-line treatment for pediatric patients with SAA who have a matched sibling donor is hematopoietic stem cell transplantation (HSCT). If a suitable donor is unavailable, IST with antithymocyte globulin antithymocyte globulin: ATG is an immunosuppressant, a drug that lowers the body's immune response. It is typically used with cyclosporine as the first-line immunosuppressive therapy (IS) to treat patients with acquired aplastic anemia. In some cases it is used as a treatment for patients with MDS and PNH. and cyclosporine cyclosporine: Cyclosporine is used along with antithymocyte globulin (ATG), another immunosuppressant, for treating aplastic anemia and some other forms of bone marrow failure. is the alternative up-front treatment.2,3 Although EPAG is approved by the US Food and Drug Administration as part of up-front aplastic anemia IST for children aged ≥2 years, its use in pediatrics is somewhat controversial.4 A subgroup analysis was performed in children (aged <18 years) enrolled in a prospective nonrandomized phase 2 study of EPAG that was added to standard IST for treatment-naive SAA. The study found that the addition of EPAG did not improve overall or complete response rates, in contrast to adult patients, who had a significantly improved response.5 However, in the only randomized study for pediatric patients, the addition of EPAG improved the complete response rate at 4 months (31% compared with 12%) but did not improve overall response (65% vs 53%) at 4 months, nor overall or event-free survival at 3 years.6 Because of these mixed results, current recommendations from the North American Pediatric Aplastic Anemia Consortium do not support the use of EPAG in the treatment of pediatric SAA.2,3
The potential for clonal evolution to myeloid malignancy remains a significant concern in pediatric patients because of their anticipated long life span after achieving remission. Currently, there is no evidence indicating that adding EPAG increases the risk of high-risk clonal evolution in treatment-naive settings, although it may lead to earlier events.7,8 In the refractory setting, EPAG has been shown to potentially increase the risk of evolution. Although the risk of clonal evolution has not been demonstrated to be higher in children treated with EPAG + IST vs IST alone, most studied patients have been adults, and there remains overall a paucity of pediatric-specific data; extended follow-up is necessary to fully understand this long-term risk.
Because of concerns regarding the long-term durability of the response and the risk of clonal evolution after IST in pediatric patients, HSCT is increasingly used in both the treatment-naive and the R/R settings. Data using matched unrelated donor HSCT as a frontline therapy are promising, and its use remains under investigation in the TransIT trial (ClinicalTrials.gov identifier: NCT05600426).9,10 However, HSCT is invasive and involves longer hospital admission times, potentially making IST a preferred option for some patients and families seeking treatment with minimal disruption to daily life.
This phase 2 clinical trial represents the only prospective study utilizing EPAG + IST in pediatric patients with R/R SAA. Although the addition of EPAG to IST did not benefit treatment-naive patients, the data suggest some potential benefits in R/R disease. EPAG has a generally favorable side-effect profile, with reversible hepatotoxicity being the main concern, the rates of which do not appear significantly different between adults and pediatric patients.4 Of note, discontinuation rates on ESCALATE were high, likely reflecting both a more cautious approach in children and a tendency to move earlier to HSCT. The study has limitations, including a small sample size (only 14 patients in the R/R arm) and a short follow-up time. Data on previous therapy were also missing in the R/R arm, and therefore it is not clear whether these patients were previously exposed to EPAG.
In the treatment-naive cohort, patients treated with EPAG + IST had a lower-than-expected ORR of 48.6%. These data seem to support previous studies showing a lack of overall hematologic improvement in pediatric patients with SAA treated with EPAG + IST compared to IST alone. In the R/R setting, there appeared to be a more favorable ORR. However, given the low patient numbers and the lack of a comparator arm, we cannot, at this time, make definitive conclusions regarding its general use for the treatment of pediatric patients with SAA. Future studies directly comparing the EPAG + IST combination to IST alone vs HSCT may provide further clarification.