Final Analysis of a Phase II Study of Intrapatient Dose-Escalation of Eltrombopag in Patients Receiving Azacitidine for Myelodysplasia/AML

Abstract

Background: Pre-existing thrombocytopenia in MDS/AML is worsened during the initial cycles of azacitidine (AZA) therapy, resulting in bleeding risk and possible platelet transfusion. Eltrombopag (EPG) is an oral TPO-receptor agonist. In vitro, it has anti-proliferative effects on AML blasts. Aim: To assess the safety of escalated doses of EPG in patients undergoing AZA for MDS/AML Method An investigator-initiated phase-II, single arm, study of EPG with AZA. Inclusion: relapsed or de-novo MDS/CMML/AML (blasts 5-30%); or symptomatic cytopenia; or blasts 31-50% if >/=65 years or previously-treated disease; and platelets Result Of 25 patients, 10 had prior therapy, which was chemo in 7; of these 6 had blasts >/=10%, 2 with blasts 20% or above. Of the 15 de-novo patients, 7 had blasts >/=20% (AML) and a further 2 had blasts between 10 and 19%. The median platelet count was 38x10^9/L (range 8-127). A median 11(2-24) cycles AZA and 6 cycles of EPG were delivered. One patient developed GrII EPG-related LFT abnormalities (resolved). Grade 3 fatigue was attributed to the combination in one patient. Thrombocytosis (>450 x109/L) resulting in EPG cessation occurred in 6 (at 50, 50, 150 and three at 200mg), without complications. 10 patients experienced reversible skin yellowing. Response/improvement was seen in 18 (72%): 7CR, 3CRm, 5HI-P,1 HI-N,2 with >50% blast reduction from >20% (8%). 5 patients had progression at first response. There were 19 events in total (17 progressions, 2 with worsening haematology). Median PFS was 12.0 months (95% CI 5.6 to 24.3 months). Median OS was 15.3 months (95% CI 11.9 to 31.7 months). Platelet improvement was seen in 54% (13/24) of patients with baseline platelets <100 at median (range) at 46d (7-107) following commencement of AZA. Only one patient (4%) had an improvement in platelets following the monotherapy phase. Conclusion Eltrombopag could be safely delivered at these doses. A phase III international study has commenced to better define the role of this combination as supportive care for patients undergoing treatment with azacitidine. Table:Characteristics and best responses observed.MDS/AML CharacteristicsBest ResponseMDS <20% Blasts, De Novo (N=7)5CR, 1SD, 1 HI-NAML >/=20%, De Novo (N=8)1CR, 1PR, 3 Hi-P, 1SD, 2 PDPrior therapy for MDS/AMLBlasts <20% (N=7)1CR, 3CRm, 1SD, 1PD, 1Hi-PPrior therapy for MDS/AMLBlasts >/=20% (N=3)2PD, 1 Hi-P Figure: Overall survival of the trial population. Figure:. Overall survival of the trial population. Disclosures Dickinson: GSK: Consultancy; Celgene: Honoraria. Off Label Use: Eltrombopag for MDS. Sardjono:GSK: Employment. Seymour:Celgene: Consultancy, Honoraria, Speakers Bureau. Kenealy:Celgene: Honoraria, Research Funding. Prince:Celgene: Consultancy, Honoraria, Research Funding.

Phase Ib study of eltrombopag and azacitidine in patients with high‐risk myelodysplastic syndromes and related disorders (the ELASTIC study)

“…Based on our data, we could have concluded that eltrombopag and azacitidine is a safe combination. Notably, similar conclusions were drawn from two other early phase studies of azacitidine/eltrombopag in MDS/AML 12,20 . However, we are mindful that the Phase III SUPPORT study raised concerns about safety and efficacy of the combination and that patients on azacitidine should not receive eltrombopag as part of routine care.…”

Azacitidine with or without eltrombopag for first-line treatment of intermediate- or high-risk MDS with thrombocytopenia

“…[15][16][17]32 There were no indicators that would predict the outcome of this phase 3 trial. 18,19 Preclinical and single-agent clinical studies of eltrombopag suggest that as a single agent, eltrombopag suppresses malignant myeloid blast proliferation [33][34][35][36] ; hence, the findings of this trial were unexpected. One hypothesis for our findings is a potential inhibition of the effects of azacitidine by eltrombopag when given concomitantly.…”

“…[15][16][17] Results of phase 1 and 2 trials have suggested that the combination of eltrombopag with azacitidine is feasible and well tolerated. 18,19 Additionally, a phase 1/2 study in lower risk MDS patients showed that the combination of another TPO-RA, romiplostim, with azacitidine was well tolerated, although blast cell counts were transiently increased in some patients. 20 Here, we report the Study of Eltrombopag in Myelodysplastic Syndromes Receiving Azacitidine (SUPPORT), a phase 3 trial investigating the efficacy and safety of eltrombopag as platelet supportive care, in patients with intermediate-to high-risk MDS and thrombocytopenia who were receiving azacitidine.…”

Alternatives, and adjuncts, to prophylactic platelet transfusion for people with haematological malignancies undergoing intensive chemotherapy or stem cell transplantation

“…Thirty-five trials were not RCTs (Bauman 2011; Berstein 2002; Castaman 1997; Dickinson 2014; Elinoff 2014; Frey 2012; Gerrits 2015; Knoefler 2013; Kristensen 1993; Liesveld 2013; Mittelman 2012; Nash 2000; NCT00358540; NCT00472290; NCT00922883; NCT01194167; NCT01328587; NCT01500538; NCT01516619; NCT01550185; NCT01757145; NCT01791101; NCT01957176; NCT01980030; NCT02046291; NCT02323178; Olnes 2012; Palmblad 2008; Svensson 2014; Townsley 2015; Will 2009a; Will 2009b; Wolff 2001; Wu 2014; Xu 2008).…”