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

Abstract

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/m2 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/m2 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.

GATA1 insufficiencies in primary myelofibrosis and other hematopoietic disorders: consequences for therapy

“…The observation that Gata1 low HSC express reduced levels of p27 (Kipl) a protein downstream to the Rac signaling lead to the discovery that the Rac activator Aplidin, a natural compound isolated from a marine tunica also known as plitidepsin, cured myelofibrosis in this mouse model [101]. Unfortunately, the following clinical trial in PMF patients was ineffective [102]. …”

Plitidepsin: design, development, and potential place in therapy

“…With respect to hematological malignancies, a Phase II trial (APL-B-020-10) of 11 patients with primary or secondary myelofibrosis was concluded early due to lack of efficacy 37. Antitumor activity seems to be greater in lymphoid neoplasms.…”

“…Two hundred and seventy six patients (1,283 cycles) were treated with the fortnightly schedule, and 164 patients (363 cycles) with the weekly schedule 32,37–45…”

“…Due to these reactions, all subsequent Phase II trials since February 2004 have included premedication with both anti-H1 and anti-H2 type antihistamines and glucocorticoids. Despite this prophylaxis, the rate of occurrence of serious reactions in all patients has remained unchanged overall, and only grade 1 reactions have decreased 32,37–45. In a phase II study37 using plitidepsin and dacarbazine as first-line therapy for advanced melanoma, hypersensitivity reactions were increased when using the combination therapy compared to plitidepsin as single agent.…”

Study on the anti-tumor mechanism of Meretrix meretrix glycopeptide

“…For example, a peptide from M. meretrix has been reported to strongly inhibit the growth of human gastric gland carcinoma cells [1] and a M. meretrix derived peptide, Mere15 (MW:15kDa) inhibits metastasis of human lung cancer A549 cell line via down-regulating matrix metalloproteinases to tumor cell apoptosis [2.3]. These researches suggest that it is a promising strategy to search antitumor drugs from the marine organisns, and the mechanism of action is complex and diverse [4][5][6][7]. In our previous study, we have found that MGP0501 possesses antitumor activity in vitro and vivo [8].…”