The addition of thrombopoietin receptor agonists (TPO-RAs) to immunosuppressive therapy (IST) improves the hematologic response rate and quality in patients with severe aplastic anemia (SAA). However, no studies have yet reported on whether there are differences in the efficacy of TPO-RAs. Here, we retrospectively analyzed the clinical data of SAA patients who received hetrombopag (HPAG) or eltrombopag (EPAG) as part of first-line standard IST to compare the efficacy. Sixty-seven patients were enrolled in the HPAG group and 42 patients in the EPAG group. The overall hematologic response (OR) rates of the HPAG group at 3 and 6 months after IST were 50.7% and 65.6%, respectively, close to that of the EPAG group (50%, p = 0.973; 73.8%, p = 0.494). The rates of complete response (CR) at 3 and 6 months were 13.4% and 31.3% in the HPAG group, respectively, which were like those in the EPAG group (11.9% and 28.6%), with no statistical difference (p = 1.00 and 0.59). The median time to first response (3.0 vs. 3.2 months, p = 0.79) was similar in HPAG and EPAG. The overall survival (OS) rates were 91.0% and 92.8% in the HPAG group and EPAG group (p = 0.53), respectively. Monosomy 7 was detected in one patient in the EPAG group and her disease transformed into acute myelocytic leukemia (AML) at 25 months after ATG treatment. One patient in HPAG had trisomy 8 at 9 months of ATG treatment, and bone marrow examination showed no disease progression.

CONCLUSION:

The addition of HPAG to standard IST in SAA patients showed similar response rates and response quality to that of EPAG. HPAG could be an alternative to EPAG for the first-line treatment of SAA patients.

Introduction: Eltrombopag (EPAG), a thrombopoietin receptor agonist, was approved for the treatment of severe aplastic anemia (SAA) combined with immunosuppressive therapy (IST). However, EPAG contains a typical biphenyl structure, which causes liver function damage. Methods: Twenty patients with SAA who were intolerant or refractory to EPAG were enrolled in a multicenter prospective registry of the Chinese Eastern Collaboration Group of Anemia (ChiCTR2100045895) from October 2020 to June 2023. Results: Eight patients who were ineffective to EPAG, six with kidney impairment, and nine with abnormal liver function (two with concomitant liver and kidney impairment) were converted to avatrombopag (AVA) therapy with the median duration of AVA treatment was 6 (3-24) months. 17 cases (85%) achieved trilineage hematological response (HR): complete remission (CR) in 3 cases (15%), good partial remission (GPR) in 4 cases (20%), partial remission (PR) in 10 cases (50%), and no response (NR) in 3 cases (15%). The median time to response was 1.7 (0.5-6.9) months, with 16 cases (94%) achieving response within six months and 17 cases (100%) within 12 months. 9 cases (50%) achieved transfusion independence. AVA converted treatment was associated with higher neutrophil counts (0.8×109/L vs 2.2×109/L, p=0.0003), platelet counts (11×109/L vs 39×109/L, p=0.0008), hemoglobin count (59g/L vs 98g/L, p=0.0002), red cell count (1.06×1012/L vs 2.97×1012/L, p=0.001), and absolute reticulocyte count (31.99 ×109/L vs 67.05×109/L p=0.0004) were all significantly elevated compared with the pre-treatment level. After the conversion to AVA therapy, liver and kidney function indexes were maintained within the normal range, no AVA related grade 2 or higher adverse events occurred, and no thrombotic events occurred. Conclusion: The conversion to AVA was an optimal choice for patients with SAA who were EPAG intolerant or refractory. Clinical trial registration: http://www.chictr.org.cn/showproj.html?proj=125480, identifier ChiCTR2100045895.

Preventing chemotherapy-induced thrombocytopenia could avoid chemotherapy dose reductions and delays. The safety and maximum tolerated dose of eltrombopag, an oral thrombopoietin receptor agonist, with gemcitabine-based therapy was evaluated. Patients with advanced solid tumors and platelets ≤300 × 10(9) /L receiving gemcitabine plus cisplatin or carboplatin (Group A) or gemcitabine monotherapy (Group B) were randomized 3:1 to receive eltrombopag or placebo at a starting dose of 100 mg daily administered on days -5 to -1 and days 2-6 starting from cycle 2 of treatment. Nineteen patients (Group A, n = 9; Group B, n = 10) received eltrombopag 100 mg and seven (Group A, n = 3; Group B, n = 4) received matching placebo. Nine eltrombopag patients in Group A and eight in Group B had 38 and 54 occurrences of platelet counts ≥400 × 10(9) /L, respectively. Mean platelet nadirs across cycles 2-6 were 115 × 10(9) /L and 143 × 10(9) /L for eltrombopag-treated patients versus 53 × 10(9) /L and 103 × 10(9) /L for placebo-treated patients in Groups A and B, respectively. No dose-limiting toxicities were reported for eltrombopag; however, due to several occurrences of thrombocytosis, a decision was made not to dose-escalate eltrombopag to >100 mg daily. In Groups A and B, 14% of eltrombopag versus 50% of placebo patients required chemotherapy dose reductions and/or delays for any reason across cycles 3-6. Eltrombopag 100 mg once daily administered 5 days before and after day 1 of chemotherapy was well tolerated with an acceptable safety profile, and will be further tested in a phase II trial. Fewer patients receiving eltrombopag required chemotherapy dose delays and/or reductions compared with those receiving placebo.

INTRODUCTION:

Immune thrombocytopenia (ITP) is a disease characterized by low platelet counts that in children commonly follows an acute self-limiting course but becomes chronic (cITP) in approximately 25% of cases. Quality of life of patients and families is negatively affected by restriction of age-appropriate activities, hemorrhagic manifestations, fear of bleeding, or therapeutic complications (Blanchette 2010). Eltrombopag is an oral thrombopoietin receptor agonist approved for treatment of cITP; PETIT is a 24-week open-label and randomized, placebo-controlled trial of eltrombopag in children with cITP who failed an initial therapy and have platelets <30,000/μL. We report preliminary health-related quality of life (HRQoL) results from PETIT derived from applying the Kids' ITP Tools (KIT; Barnard 2003; Klaassen 2007).

METHODS:

Initially, 15 patients were enrolled in 3 age cohorts (12–17, 6–11, 1–5 years) and received open-label eltrombopag. Additional patients in each cohort were enrolled into the randomized phase once initial safety and efficacy data became available from the open-label phase. The KIT is scored from 0 (worst) to 100 (best), and was completed by patients in the 2 older cohorts and by parents/guardians of all patients at study entry and treatment weeks 6, 12, and 24.

RESULTS:

HRQoL data for the 15 open-label patients, 5 from each cohort, are presented. At baseline, 9 (60%) patients had platelets ≤15,000/μL and the incidence of bleeding WHO grades 1–4 and 2–4 was 87% (13/15) and 33% (5/15), respectively. All patients completed 24 weeks of treatment. The mean KIT score at baseline for the 10 patients who were 6–17 years old was 65.7 (range, 42.3–85.6; median, 66.3; parents/guardians mean, 61.9) (Figure 1); the mean baseline score reported by parents on behalf of their children (n=15) was 66.5 (range, 43.0–93.3; median, 64.4). At Week 24, among the 10 patients completing the KIT, 9 had higher scores at Week 24 compared to baseline (mean, 19.6-point improvement; median, 19.2; range, 4.8–37.5). Eight of 9 patients had at least a 5-point increase in score (mean, 21.4-point improvement; median, 20.2; range, 6.7–37.5); an additional patient had a score increase of 4.8 points (80.8 at baseline to 85.6 at Week 24). The remaining patient, who had severely fluctuating platelet counts, had a reduced KIT score compared with baseline by 12.5 points (76.9 at baseline, 64.4 at Week 24). Among parent/guardian assessments, 13/15 reported improved KIT scores at Week 24 (mean, 17.9-point improvement; median, 15.4; range, 2.9–41.1; 1 score was last observation carried forward [LOCF]) (Figure 2). Eleven of 15 had at least a 5-point increase in score (mean, 20.5-point improvement; median, 15.7; range, 11.5–41.1). Two parents scored lower than baseline at 24 weeks: parents of the patient with fluctuating platelets (14.4-point reduction; 64.4 at baseline, 50.0 at Week 24) and of a 4-year-old who failed to respond to eltrombopag (40.4-point reduction; 93.3 at baseline, 52.9 at LOCF [Week 12]).

DISCUSSION/CONCLUSIONS:

Preliminary data suggest that treatment with eltrombopag is associated with improvements in HRQoL in children with cITP. Final results of PETIT should further the understanding of the potential of eltrombopag treatment to improve HRQoL in pediatric patients and further validate the use of the KIT in assessing treatment outcomes of childhood cITP.

In absence of direct comparison, we conducted an indirect-comparison meta-analysis to evaluate the efficacy and safety of thrombopoietin-receptor agonists(TPO-RAs) in treatment of pediatric persistent or chronic immune thrombocytopenia(ITP). PubMed, Embase, Cochrane Library, Clinical Trials.gov, China National Knowledge Infrastructure, and Chinese Biomedical Literature Database were searched from their earliest records to May 2017. Randomized controlled trials comparing the TPO-RAs with placebo in pediatric ITP were included. Outcomes included overall response rate(primary), durable response, overall or clinically significant bleeding, the proportion of patients receiving rescue medication, and safety. Five randomized placebo-controlled studies(N = 261) were analyzed. The overall response[Risk Ratio(RR) 0.57, 95% confidence interval(CI) 0.21-1.56], the incidence of adverse events (RR 0.96, 95%CI 0.66-1.39), durable response(RR 2.48, 95%CI 0.31-19.97), and the proportion of patients receiving rescue treatment(RR 0.73, 95%CI 0.20-2.73) were similar between eltrombopag and romiplostim group. Nevertheless, eltrombopag might have lower risk of overall bleeding(RR 0.43, 95%CI 0.23-0.80) and clinically significant bleeding(RR 0.33, 95%CI 0.12-0.89) than romiplostim. This meta-analysis suggests that eltrombopag might be similar to romiplostim in efficacy and safety, but seems to reduce the risk of bleeding compared to romiplostim. Furthermore, cost of the treatment, comorbidity of patients and drug compliance should also be considered in clinical decision making.

AIM To evaluate the effect of eltrombopag on cardiac repolarization and to characterize the relationship between plasma eltrombopag concentrations and change in QTc. METHODS This was a double-blind, placebo- and active-controlled, randomized, balanced four-period, crossover study in healthy men and women. Subjects were randomized to receive eltrombopag 50 mg and 150 mg, moxifloxacin 400 mg (positive control) and placebo in one of four sequences. RESULTS Eighty-seven subjects entered the study and 48 completed. There was no prolongation of QTc (Fridericia) following eltrombopag treatment, as the upper limit of the 90% confidence interval (CI) for the time-matched change from baseline in QTcF between drug and placebo (ddQTcF) did not exceed 10 ms for eltrombopag at either dose. Maximum observed mean treatment difference was 2.29 ms (90% CI 0.34, 4.24) for eltrombopag 150 mg at 1 h post-dose and 11.64 ms (90% CI 9.64, 13.64) for moxifloxacin 400 mg at 4 h. Eltrombopag Cmax and AUC(0,24 h) increased in a dose proportional manner between 50 mg and 150 mg after 5 days' dosing. Proportions of subjects with adverse events were similar across treatments (52-66% of subjects). Most withdrawals (26/39 subjects) were due to elevated platelets. Three subjects were withdrawn for ventricular premature beats (one following each active treatment) reported as related to the study drug. CONCLUSIONS No clinically significant QTc prolongation was observed for eltrombopag at therapeutic and supratherapeutic doses. © 2010 The British Pharmacological Society.

The PETIT (Eltrombopag in Pediatric Patients with Thrombocytopenia from Chronic ITP) trial showed that in children aged 1-17 years with chronic or persistent immune thrombocytopenia (ITP), eltrombopag improved platelet counts, decreased clinically significant bleeding and reduced rescue medication need. We report the health-related quality of life (HRQoL) results from the PETIT study using the Kids' ITP Tools (KIT). A limitation was that PETIT was not powered for the HRQoL analysis. Eltrombopag did not impact children's HRQoL assessed by the KIT. Although median KIT scores in children treated with eltrombopag with platelet responses were numerically higher compared with non-responders in some age groups, the interquartile ranges overlapped.

Because Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) patients have microthrombocytopenia, hemorrhage is a major problem. We asked whether eltrombopag, a thrombopoietic agent, would increase platelet counts, improve platelet activation, and/or reduce bleeding in WAS/XLT patients. In 9 WAS/XLT patients and 8 age-matched healthy controls, platelet activation was assessed by whole blood flow cytometry. Agonist-induced platelet surface activated glycoprotein (GP) IIb-IIIa and P-selectin in WAS/XLT patients were proportional to platelet size and therefore decreased compared with controls. In contrast, annexin V binding showed no differences between WAS/XLT and controls. Eltrombopag treatment resulted in an increased platelet count in 5 out of 8 patients. Among responders to eltrombopag, immature platelet fraction in 3 WAS/XLT patients was significantly less increased compared with 7 pediatric chronic immune thrombocytopenia (ITP) patients. Platelet activation did not improve in 3 WAS/XLT patients whose platelet count improved on eltrombopag.

IN CONCLUSION:

(1) the reduced platelet activation observed in WAS/XLT is primarily due to the microthrombocytopenia; and (2) although the eltrombopag-induced increase in platelet production in WAS/XLT is less than in ITP, eltrombopag has beneficial effects on platelet count but not platelet activation in the majority of WAS/XLT patients. This trial was registered at www.clinicaltrials.gov as #NCT00909363.

We report the first successful treatment with the thrombopoietin receptor mimetic eltrombopag in a patient with severe aplastic anaemia (SAA) associated with HIV infection, thereby avoiding the use of standard immunosuppressive agents for treatment of SAA. Eltrombopag induced a trilineage haematological response. We also show that eltrombopag had an immunomodulatory role with a decrease in proinflammatory T helpers (Th1 and Th17 cells) with increased T-regulatory cell/T-helper ratio, thus contributing to recovery of haemopoiesis.

BACKGROUND:

Engraftment of neutrophils and platelets after hematopoietic stem cell transplant (HSCT) is imperative for optimal outcomes. Eltrombopag has been used in adults after HSCT to boost platelet production. Its use in pediatric post HSCT patients has been limited.

METHODS:

The clinical and laboratory details of a post autologous HSCT patient were fetched by a retrospective review of the records.

RESULTS:

A 5-year old male child had primary thrombocytopenia post autologous HSCT for refractory Hodgkin lymphoma. Although the stem cell dose infused was adequate, the child had a delay in the engraftment of platelets. After ruling out the causes of post HSCT thrombocytopenia, eltrombopag was started for the child. With the use of eltrombopag, normal thrombopoiesis was restored in the child.

CONCLUSION:

Eltrombopag was effective and safe in overcoming post-HSCT primary thrombocytopenia in our patient.