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Evaluation of plitidepsin in patients with primary myelofibrosis and post
polycythemia vera/essential thrombocythemia myelofibrosis: results of preclinical
studies and a phase II clinical trial
#MMPMID25768401
Pardanani A
; Tefferi A
; Guglielmelli P
; Bogani C
; Bartalucci N
; Rodríguez J
; Extremera S
; Pérez I
; Alfaro V
; Vannucchi AM
Blood Cancer J
2015[Mar]; 5
(3
): e286
PMID25768401
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Previous data established that plitidepsin, a cyclic depsipeptide, exerted
activity in a mouse model of myelofibrosis (MF). New preclinical experiments
reported herein found that low nanomolar plitidepsin concentrations potently
inhibited the proliferation of JAK2V617F-mutated cell lines and reduced colony
formation by CD34+ cells of individuals with MF, at least in part through
modulation of p27 levels. Cells of MF patients had significantly reduced p27
content, that were modestly increased upon plitidepsin exposure. On these
premise, an exploratory phase II trial evaluated plitidepsin 5?mg/m(2) 3-h
intravenous infusion administered on days 1 and 15 every 4 weeks (q4wk). Response
rate (RR) according to the International Working Group for Myelofibrosis Research
and Treatment consensus criteria was 9.1% (95% CI, 0.2-41.3%) in 11 evaluable
patients during the first trial stage. The single responder achieved a red cell
transfusion independence and stable disease was reported in nine additional
patients (81.8%). Eight patients underwent a short-lasting improvement of
splenomegaly. In conclusion, plitidepsin 5?mg/m(2) 3-h infusion q4wk was well
tolerated but had a modest activity in patients with primary, post-polycythaemia
vera or post-essential thrombocythaemia MF. Therefore, this trial was prematurely
terminated and we concluded that further clinical trials with plitidepsin as
single agent in MF are not warranted.
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