Promacta and Vidaza

[Birgitta-A]

Hi All,
Here are results from a study with Promacta in combination with Vidaza.

MDS Conference Berlin 2013 P-276
High doses of eltrombopag (Promacta) are well-tolerated in conjunction with azacitidine (Vidaza) and demonstrate encouraging activity in patients with MDS and AML
M. Dickinson1, K. Herbert1, C. Sardjono2, T. Le2, E. Link2, D. Zannino2, S. Ruell3, J.F. Seymour1, M. Kenealy4, H.M. Prince5. 1Haematology Dept., Peter MacCallum Cancer Centre, Melbourne; 2Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Melbourne; 3Clinical Trial Unit, Peter MacCallum Cancer Centre, Melbourne; 4Blood Group, Cabrini Medical Centre, Melbourne; 5Peter MacCallum Cancer Centre, Haematology Dept., Melbourne, Australia

Background: Pre-existing thrombocytopenia in MDS/AML is exacerbated during the initial cycles of azacitidine (AZA) therapy, resulting in bleeding risk and possible platelet transfusion.

Introduction: Eltrombopag is an oral TPO-receptor agonist. In vitro, it has anti-proliferative effects on AML blasts. Hence, it may have clinical utility in MDS/AML in combination with azacitidine.

Purpose: To assess safety and tolerability of high doses of eltrombopag in combination with azacitidine in MDS/AML.

Materials and Methods: This is a phase-II, single arm, dual-centre, open-label study of escalating doses of eltrombopag with AZA. Inclusion required: a diagnosis of relapsed or de-novo MDS/CMML/AML with marrow blasts 5-30%; or symptomatic cytopenia; or blasts 31- 50% if either ≥65 years or previously-treated disease; and platelets ≤150×109/L. The primary endpoint was the rate of grade III/IV nonhaematological events related to therapy.

Secondary endpoints were AE rates, overall response rates, and survival. Eltrombopag 50mg/day continuously was begun with AZA 75mg/m2 d1-5, & 8-9 on a 28d cycle.

For patients with platelets ≤100 there was a 14d pre-treatment with eltrombopag monotherapy. Intrapatient dose-escalation of eltrombopag to 100mg, 200mg and 300mg fortnightly occurred in those with cycle start platelet counts <75 or nadir ≤50. Eltrombopag was ceased after 6Mo but could be restarted for severe thrombocytopenia at investigator discretion.

Results: 17 of a planned 25 patients have been recruited; 6 had received prior therapy for MDS/AML, 11 had baseline marrow blasts ≥10%.Median baseline platelet count was 37.5 (range 17-127). A median of 8 (2-18) cycles of AZA and 5 (1-11) cycles of eltrombopag have been delivered.

One patient developed grade-III eltrombopag-related LFT abnormalities (resolved). There were no other grade III/IV AEs attributable to the combination. Thrombocytosis resulting in eltrombopag cessation occurred in 4 patients (at 50, 50, 150 and 200mg), without complications. 10 patients experienced reversible skin yellowing.

Activity was seen in 76%: 4CR, 3CR-marrow, 3 HI-P (2 unconfirmed), 1 HIE (unconfirmed), 2 with >50% blast reduction from >20% (1 also with Hi-P unconfirmed).

2 patients with previously-treated AML progressed at cycle 2 and one with untreated AML progressed at cycle 10.

Platelet improvement was seen in 53% (8/15) of patients with baseline platelets <100 at median (range) at 63d (21-106) following commencement of AZA. One patient (7%) had an improvement in platelets following the monotherapy phase.

Conclusions: A strategy of intra-patient dose escalation of eltrombopag from 50-300mg with AZA has promising response rates, is well-tolerated and has an acceptable rate of AE. However, the 14d 50mg eltrombopag monotherapy pre-phase was insufficient to lead to consistent haematological improvement.
Kind regards
Birgitta-A