Tamoxifen Reduces Allele Burden of Patients With Myeloproliferative Neoplasms

Vicki Moore, PhD

January 10, 2024

In a clinical trial evaluating the use of tamoxifen in patients with stable myeloproliferative neoplasms (MPNs), 3 patients showed a 50% or greater reduction in mutant allele burden at 24 weeks. This and other results from the study appeared to support further investigation of this agent in this population, but with consideration of possible thrombotic risk. Study results were reported in the journal Nature Communications.

The multicenter, single-arm, phase 2 TAMARIN study (Eudra CT Identifier: 2015-005497-38) examined the safety and activity of tamoxifen in patients with stable MPNs. Included patients had no prior thrombotic events and had a mutant allele burden ≥20% in peripheral blood samples involving JAK2^V617F, a CALRinsertion of 5 bp (exon 9), or a CALR deletion of 52 bp (exon 9). Tamoxifen was given at 20 mg/d orally, with progressive escalation to 40 mg/d based on tolerance and efficacy, and with treatment lasting for 24 weeks.

The study’s primary endpoint was a ≥50% reduction in the mutant allele burden in peripheral blood at 24 weeks, with trial success involving at least 3 patients having met this outcome. Several secondary and exploratory outcomes were also evaluated.

These results warrant further investigation of tamoxifen as potential therapeutic for MPN in larger studies, after careful consideration of the risk of thrombosis.

There were 38 patients recruited into the study, with 32 patients completing 24 weeks of treatment. In the total population of 38 patients, 36.8% had essential thrombocythemia, 28.9% had polycythemia vera, 15.8% had primary myelofibrosis, 13.2% had post-polycythemia vera myelofibrosis, and 5.3% had post-essential thrombocythemia myelofibrosis. The overall population had a mean age of 66.3 years (range, 50.0-87.0 years).

There were 3 patients who reached the primary outcome of a ≥50% reduction in mutant allele burden at 24 weeks. Therefore, this study was considered a success in terms of its primary outcome. An additional 5 patients met a secondary outcome of achieving a ≥25% reduction in mutant allele burden, of whom 3 patients had JAK2^V617F mutations.

In this study, there were 4 serious adverse effects reported, including 1 grade 3 urinary tract infection, a grade 1 intracranial hemorrhage, and 2 vascular disorders. The events of vascular disorders consisted of 1 case of superficial thrombophlebitis and 1 thromboembolic event, with both of these events considered potentially related to tamoxifen use. There was 1 discontinuation in a patient after a thrombotic event, and discontinuation due to toxicity was reported with 11 patients.

The study investigators additionally performed analyses using hematopoietic stem/progenitor cells that revealed distinctive molecular signatures in responders and nonresponders at baseline. In responders, increased expression of genes associated with JAK-STAT signaling and oxidative phosphorylation appeared to become downregulated in the presence of tamoxifen.

“These results warrant further investigation of tamoxifen as potential therapeutic for MPN in larger studies, after careful consideration of the risk of thrombosis,” the study investigators wrote in their report.

References: Fang Z, Corbizi Fattori G, McKerrell T, et al. Tamoxifen for the treatment of myeloproliferative neoplasms: a phase II clinical trial and exploratory analysis. Nat Commun. 2023;14(1):7725. doi:10.1038/s41467-023-43175-5

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