Tamoxifen, a selective estrogen receptor modulator, shows potential as a line of treatment in some patients with myeloproliferative neoplasms.
Findings from a phase 2 study support the further investigation of tamoxifen (Soltamox), a selective estrogen receptor modulator (SERM), as a treatment option in patients with myeloproliferative neoplasms (MPNs), with extra consideration for thrombotic risk.1
A total of 38 patients with MPNs with mutated JAK2V617F, CALRins5, or CALRdel52 peripheral blood allele burden greater than 20% were recruited, and 32 patients completed 24 weeks of treatment. A greater than 50% reduction in mutant allele burden at 24 weeks was observed in 3 patients, and a 25% or greater reduction in mutant allele burden at 24 weeks was observed in 5 patients.
An exploratory analysis of hematopoietic stem/progenitor cell (HSPC) transcriptome identified a difference between responders and non-responders. Investigators observed that in responder HSPCs, there was a high baseline expression of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling and oxidative phosphorylation genes, which tamoxifen appeared to downregulate.
“The perfect segregation of the HSPC transcriptome from responders and non-responders at baseline could serve in the future as a platform for the stratification of patients based on their likelihood to respond to tamoxifen and for the identification of predictive biomarkers of response, if prospectively validated,” study authors wrote in findings published in Nature Communications.
“These results suggest that the metabolic effects of SERMs in cancer might be underappreciated and propose ways to modulate pathogenic JAK-STAT signaling through metabolic rewiring. These results warrant further investigation of tamoxifen as potential therapeutic for MPN in larger studies, after careful consideration of the risk of thrombosis,” study authors wrote.
Patients with essential thrombocythemia (ET), polycythemia vera (PV), primary myelofibrosis (MF), post-PV MF, and post-ET MF were included in the study. The primary end point was a mutant allele burden reduction of greater than 50% at 24 weeks. The secondary end points included mutant allele burden reduction between 25% and 50% at 24 weeks, a greater than 50% reduction at 12 weeks, thrombotic events, toxicities, and hematological response.
Thrombotic adverse events (AEs) potentially related to tamoxifen were reported in 2 patients, and 1 patient discontinued treatment due to this AE. Investigators identified that the thrombotic events only occurred in non-responders, so identifying responders before initiating treatment should help reduce risks to patients.
Regarding safety, 11 additional patients discontinued study treatment due to toxicity. A grade 1 intracranial hemorrhage unrelated to tamoxifen was reported. No patient deaths were reported. Complete symptoms response was observed in 19% of patients, while 71.4% of patients had a partial symptom response, and 9.5% of patients had no response.
The results of this study warrant further exploration into tamoxifen as a treatment option for MPNs and further investigation of SERMs with lower thrombotic risks.