Efficacy and Safety of Eltrombopag for the Treatment of Thrombocytopenia of Low and Intermediate-1 IPSS Risk Myelodysplastic Syndromes: Interim Analysis of a Prospective, Randomized, Single-Blind, Placebo-Controlled Trial (EQoL-MDS)

The increased risk of bleeding in myelodysplastic syndromes (MDS) is due to low platelet (PLT) counts and abnormalities of PLT morphology and function. Severe thrombocytopenia occurs in about 10% of low and Int-1 International Prognostic Scoring System (IPSS) risk MDS patients in whom PLT transfusions are indicated mainly in the presence of bleeding. Short therapeutic effect and the development of refractoriness to PLT transfusions motivate research in novel treatments. Eltrombopag is an oral, non peptide, non-competitive agonist of the thrombopoetin-receptor (TPOR) which interacts selectively with the TPOR transmembrane domain to initiate TPO signaling. Eltrombopag is indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura. Its potential in increasing PLT count in lower risk MDS has not been evaluated.

We present preliminary results of a Phase II, multicentre, prospective, placebo-controlled, single blind study to evaluate the safety and efficacy of eltrombopag in low and intermediate-1 risk adult MDS patients with PLT count <30 Gi/L. Patients are included if: ECOG performance status < 4; ineligible for or relapsed or refractory to other treatments; and naive to TPO-R agonists. Secondary endpoints include differences in: changes in quality of life (QoL) scores by EORTC QLQ-C30 and QOL-E v. 3 questionnaires, frequency of PLT transfusions, incidence and severity of bleeding, and overall and leukemia-free survival. Eltrombopag or placebo (2:1 ratio) is administered to 69 patients at a 50 mg daily initial dose with 50 mg increases every 2 weeks to a target PLT count of 100 Gi/L. Dose interruptions or reductions are required for PLT >200 Gi/L or adverse events. PLT response is defined as Response (R) if: 1) baseline > 20 Gi/L: absence of bleeding and absolute increase in PLT ≥ 30 Gi/L/mm3; 2) baseline < 20 Gi/L: PLT <20 Gi/L and increase by at least 100%, not due to PLT transfusion; and Complete Response (CR) if PLT count ≥ 100 Gi/L and absence of bleeding. Bone marrow (BM) aspirate smears, cytogenetics and peripheral blood (PB) smears are performed throughout the study and blinded centralized morphology review is performed.

Seventeen patients (10 on active drug – Arm A) of mean age 64, SD 12, years are randomized and 2 are in screening at the time of the present report. Baseline mean PLT count was 14, SD 8, Gi/L. Three cases had significant bleeding (2 in Arm A, and 1 in Arm B) and 2 patients in each arm required PLT transfusions during screening. After a mean follow up of 6 months, 5 cases on the eltrombopag arm have obtained a CR (1 at day 8, 3 at day 15 with 50 mg dosing, and 1 at day 54 with 100 mg dosing) and one case is in R at 8 weeks follow-up; amongst non-responders, two have reached a 300 mg dose, the remaining are ongoing at a 100 and 150 mg dose, respectively. In Arm B, there was one case with an unstable R. In Arm A, PLT count increased by mean 68 SD 76 Gi/L (p=0.010) after 4 weeks and 114 SD 110 Gi/L (p=0.021) after 8 weeks, versus no significant change in Arm B. Furthermore, after 2 months, no bleeding occurred in Arm A (N=9) versus 3 cases with bleeding in Arm B (N=6). In fact, no PLT transfusions were required in Arm A, while 3 patients were transfused at 2 months in Arm B. At baseline, patients presented poor QoL scores. Overall, of the 9 patients in arm A reaching a 3-month follow-up, there were significant improvements in functional QoL, from baseline median score 33 (IQR 22–67) to 78 (IQR 31–92, p=0.047) and treatment-related scores from median 51 (IQR 35–66) to 74 (IQR 35–82, p=0.029). Grade III-IV adverse events (worsening of pre-existing arthritis; acute febrile enteritis) occurred in only 2 patients in Arm A, all unrelated to eltrombopag. Progressions have not been observed in Arm A, versus 1 progression in Arm B. No deaths have occurred at the time of the present analysis.

Preliminary results suggest safety of eltrombopag in terms of drug-related adverse events and disease progression in MDS patients with low and Intermediate-1 risk IPSS and thrombocytopenia. In such patients, eltrombopag treatment is effective in raising PLT counts and in reducing the risk of bleeding and is associated with significant improvements in QoL.

Off Label Use: Eltrombopag is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) .