Combination of Eltrombopag With Immunosuppressive Therapy in East-Asian Patients With Severe Aplastic Anemia

Complete response rate was defined as percentage of patients achieving complete response (CR).

Complete response was defined as subjects meeting all the three criteria on two consecutive serial blood count measurements at least one week apart but not more than four weeks apart:

• Absolute neutrophil count > 1.0 ×10^9/L
• Platelet count > 100 ×10^9/L
• Hemoglobin > 100 g/L

The participants who discontinued from the trial before Week 26 and those that received blood products prior to response assessment (7 days prior for platelet transfusions, 14 days for RBC transfusion and 21 days for growth factors) were treated as non-responders.

Complete response rate was defined as percentage of patients achieving complete response (CR).

Complete response was defined as subjects meeting all the three criteria on two consecutive serial blood count measurements at least one week apart but not more than four weeks apart:

• Absolute neutrophil count > 1.0 ×10^9/L
• Platelet count > 100 ×10^9/L
• Hemoglobin > 100 g/L

The participants who discontinued from the trial before Week 26 and those that received blood products prior to response assessment (7 days prior for platelet transfusions, 14 days for RBC transfusion and 21 days for growth factors) were treated as non-responders.

Overall response rate was defined as percentage of patients achieving complete response (CR) or partial response (PR).

Partial response (PR) was defined as blood counts no longer meeting the standard criteria for severe pancytopenia in SAA, equivalent to at least 2 of the 3 criteria below, but not sufficient for a CR:

• Absolute neutrophil count ≥ 0.5 × 10^9/L
• Platelet count ≥ 20 × 10^9/L
• Reticulocyte count ≥ 20 × 10^9/L

Complete response (CR) was defined as subjects meeting all the three criteria on two consecutive serial blood count measurements at least one week apart but not more than four weeks apart:

• Absolute neutrophil count > 1.0 ×10^9/L
• Platelet count > 100 ×10^9/L
• Hemoglobin > 100 g/L

Duration of response was derived as the time from first documented and confirmed complete response (CR) until the time of relapse or death, whichever occurred first. Duration of response was estimated using Kaplan-Meier method.

Clinical relapse was considered as the occurrence of any of the following events in a participant who had achieved a hematological response (CR) but had subsequently lost response (not explained by any other independent concomitant medical conditions) in one blood count measurements:

• Meeting again the criteria for SAA
• Requirement for transfusion again for subjects who had been transfusion independent
• Decrease in any of the peripheral blood counts to absolute neutrophil count < 0.5 x10^9/L or platelets < 20 x10^9/L.

Duration of response was derived as the time from first documented and confirmed response (either CR or PR) until the time of relapse or death, whichever occurred first. Duration of response was estimated using Kaplan-Meier method.

Clinical relapse was considered as the occurrence of any of the following events in a participant who had achieved a hematological response (CR or PR) but had subsequently lost response (not explained by any other independent concomitant medical conditions) in one blood count measurements:

• Meeting again the criteria for SAA
• Requirement for transfusion again for subjects who had been transfusion independent
• Decrease in any of the peripheral blood counts to absolute neutrophil count < 0.5 x10^9/L or platelets < 20 x10^9/L.

OS was defined as the time from the date of the first dose of study treatment to the date of death due to any cause. If a subject was not known to have died, survival was censored at the date of last contact. The distribution function of OS was estimated using the Kaplan- Meier method.

OS was defined as the time from the date of the first dose of study treatment to the date of death due to any cause. The OS rate is the estimated probability that a patient will remain event-free up to the specified time point and was obtained from the Kaplan-Meier survival estimates. If a subject was not known to have died, survival was censored at the date of last contact.

Transfusion-free interval was defined as the time from most recent RBC/platelet transfusion preceding response assessment to the date of response assessment.

Transfusion independent participants were defined as those participants who were transfusion dependent at baseline but became transfusion free for a period of ≥ 8 weeks post-baseline for RBCs.

Transfusion independent participants were defined as those participants who were transfusion dependent at baseline but became transfusion free for a period of ≥ 4 weeks post-baseline for platelets.

Clonal evolution events were assessed by karyotyping (G-banding) and FISH (Fluorescence in situ hybridization) targeting abnormalities including, but not restricted to chromosome 3q del,5q del, monosomy 7, trisomy 8 and those associated with SAA (Severe aplastic anemia), MDS (Myelodysplastic syndrome), AML (Acute myeloid leukemia). Time to clonal evolution was to be estimated using the Kaplan-Meier method.

AUClast is the area under the curve from time zero to the last measurable concentration sampling time.

Blood samples were collected from patients to assess the plasma concentrations of eltrombopag using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS) approach.

AUCtau is area under the curve calculated to the end of a dosing interval (tau) at steady-state

Blood samples were collected from patients to assess the plasma concentrations of eltrombopag using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS) approach.

Cthrough is the pre-dose concentration at the end of dose interval.

Blood samples were collected to assess the plasma concentrations of eltrombopag using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS) approach.

Eltrombopag was administered orally once daily with initial doses of 75mg/day for ≥ 12 years old and 37.5 mg/day for participants between ≥ 6 and < 12 years.

Doses could be adjusted based on platelet count every 2 weeks by decreasing it by 25 mg/day (12.5 mg/day, for participants below 12 years old) if the platelet count was above 200×10^9/L. or interrupted if platelet count rose above 400×10^9/L. In partial response participants dose could be restarted or increased to that before the decrease if platelet counts < 30 x10^9/L, Hb< 90 g/L, ANC< 0.5 x 10^9/L or participant needed transfusion. In complete response participants dose could be restarted or increased to that before decrease if blood counts dropped to not meet CR criteria.

Cmax is the The maximum (peak) observed plasma drug concentration after dose administration.

Blood samples were collected from patients to assess the plasma concentrations of eltrombopag using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS) approach.

Tmax is the time to reach maximum (peak) plasma drug concentration after dose administration.

Blood samples were collected from patients to assess the plasma concentrations of eltrombopag using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS) approach.

CLss/F is Apparent systemic (or total body) clearance at steady state from plasma.

Blood samples were collected from patients to assess the plasma concentrations of eltrombopag using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS) approach.