Long-Term Durability of Eltrombopag Clinical Benefit for Advanced Myelodysplastic Syndromes or Acute Myeloid Leukemia and Severe Thrombocytopenia (ASPIRE Part 3)

Thrombocytopenia is a common complication in patients (pts) with advanced myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) that is associated with significant morbidity, a clinically significant bleeding risk, and early death. There are only limited treatment options for this high-risk population. Previous trials (Frey et al. ASH 2012) of thrombopoietin receptor agonists (TPO-RAs) for thrombocytopenia treatment in these pts suggested reduced thrombocytopenia-associated bleeding. ASPIRE (NCT01440374) was a multicenter, phase 2 trial. Eligible pts were ≥18 years, with high-risk MDS or AML, thrombocytopenia (platelets ≤25 x 109/L) due to bone marrow insufficiency, bone marrow blasts ≤50%, and an Eastern Cooperative Oncology Group status of 0-2. Exclusion criteria included platelets ≤10 x 109/L for reasons other than bone marrow insufficiency; leukocyte count ≥25 x 109/L; previous TPO-RA treatment. Pts were severely ill, on no other anti-MDS/AML therapy, with an expected median survival of ~6 months on treatment. Part 1 was an 8-week open-label study of eltrombopag 100 mg/day with dose escalation up to 300 mg/day (Mittelman et al. ASH 2012). Part 2 was a 12-week randomized, double-blind trial, during which pts received eltrombopag or placebo (Mittelman et al. Lancet Haematol 2018). Pts who completed both parts continued to Part 3, an extension phase of 10 months (for pts from Part 1) and 9 months (for pts from Part 2) (Fig. 1A). In ASPIRE Part 2, eltrombopag reduced the frequency of clinically relevant thrombocytopenic events (CRTEs) (one or more ≥Grade 3 hemorrhagic adverse events [AEs], platelets ≤10 x 109/L, or platelet transfusions) compared with placebo during weeks 5-12 in pts with advanced MDS or AML. Here we present data on the long-term durability of clinical benefit, overall survival (OS) and progression-free survival (PFS) for Part 2 pts within Part 2 and Part 3, and safety and tolerability of eltrombopag monotherapy in pts with advanced MDS or AML. Mean pt age was 72.2 years. Pts received a median eltrombopag daily dose of 298.8 mg with a median exposure of 11.1 weeks. At baseline, 40% of pts had an abnormal karyotype and 68% were platelet transfusion-dependent. OS (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.64-1.48) and PFS (HR 0.99, 95% CI 0.68-1.43) were not significantly different between long-term eltrombopag and placebo to eltrombopag switchers in Part 3 (median OS of 4.3 months vs 4.6 months, respectively). Median PFS was 0.94 months and 1.08 months for the placebo and eltrombopag group, respectively. CRTEs were summarized by week with the proportion of pts plotted by visit. Pts experienced large variability in CRTEs during weeks 1-40 with inconclusive results due to low number of pts at some time points (Fig. 1B). Hematological improvement (HI) was defined as improvement (platelets, neutrophils, hemoglobin) on treatment compared with placebo (Cheson et al. Blood 2006). Overall, 33% of pts showed HI with long-term eltrombopag use, compared with 10% during the double-blind phase. However, HI did not reach statistical significance compared with placebo in the double-blind phase. 46% of pts completed treatment. The main reasons for treatment discontinuation were physician decision (24%) and AEs (22%). Overall, 97% of pts experienced an AE during the extension phase plus 30 days. The most common AEs (≥20% of pts) were pyrexia, nausea, diarrhea, and epistaxis. Overall, 56% of pts died, with the disease under study being the most common cause (36%), and 37% of pts had treatment-related AEs. 31% of pts experienced Grade 3 or 4 AEs. The most commonly reported (>5%) were pneumonia, febrile neutropenia, anemia, hypokalemia, and urinary tract infection. Overall, 66% of pts experienced a serious AE (SAE). The most common (≥10%) were pneumonia, pyrexia, febrile neutropenia, and sepsis. The most common fatal SAEs (≥5%) were sepsis, pneumonia, and cardiac failure. ASPIRE Part 3 did not identify any new safety signals. The most common AEs were consistent with those expected for the disease under study and with eltrombopag treatment. There was no evidence of reduced OS or PFS. More pts met the criteria for HI with long-term eltrombopag use compared with those in the double-blind phase. The large CRTE variability observed with eltrombopag during Part 3 requires further assessment in adequately powered trials of high-risk MDS or AML pts and in a less seriously ill population. Figure 1 Disclosures Mittelman: Novartis: Honoraria, Research Funding, Speakers Bureau. Platzbecker:Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Portella:Novartis: Employment. Zhu:Novartis: Employment. Selleslag:Celyad: Other: Clinical trial research (no honoraria recieved); Novartis: Consultancy, Honoraria, Speakers Bureau. OffLabel Disclosure: Eltrombopag is used for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Eltrombopag is not indicated for the treatment of patients with myelodysplastic syndrome (MDS).