TAMARIN trial: Tamoxifen for the treatment of MPN

Many therapies for myeloproliferative neoplasms (MPN) address symptom improvement without a focus on reduction in tumor size.¹ Tamoxifen, a selective estrogen receptor modulator, has been shown to induce apoptosis in multipotent hematopoietic progenitors whilst sparing normal hematopoietic stem cells; therefore, it is under investigation to target tumor size in patients with stable MPN and without previous thrombotic events.¹

Below, we summarize the phase II TAMARIN study (EudraCT 2015-005497-38) investigating tamoxifen in patients with stable MPN; no prior thrombotic events; and mutated JAK2^V617F, CALR^ins5, or CALR^del52 peripheral blood allele burden ≥20%.

TAMARIN study design¹

• In total, 38 patients were enrolled
• The primary outcome was a ≥50% decrease in mutant allele burden in peripheral blood at 24 weeks
• Secondary outcomes included a ≥25% decrease in mutant allele burden at 24 weeks and toxicities

Results¹

The baseline characteristics are shown in Table 1.

Table 1. Baseline patient characteristics*

Characteristics, % (unless otherwise specified)	Patients (N = 38)
*Adapted from Fang, et al.1
Mean age, years	66.3
Sex
Male	71.1
Female	28.9
Disease subtype
Essential thrombocythemia	36.8
Primary myelofibrosis	15.8
Post-essential thrombocythemia           myelofibrosis	5.3
Polycythemia vera	28.9
Post-polycythemia vera myelofibrosis	13.2

Efficacy¹

• Most patients (84%) completed the 24-week treatment plan
• Overall, three patients met the primary outcome
  • Three patients achieved ≥50% reduction in mutant allele burden
• Five patients showed a ≥25% decrease in mutant allele burden at 24 weeks
  • Three of these patients carried the JAK2^V617F mutation
  • The two remaining patients carried CALR^del52 and CALR^ins5 mutations, but these mutations also require increased MPL-JAK-STAT activation to be pathogenic.
• Six patients remained on treatment beyond 48 weeks

Safety¹

The safety profile was manageable and four serious adverse events (SAE) were reported:

• urinary infection (n = 2) and intracranial hemorrhage (n = 1) not considered related to treatment;
• vascular disorders (n = 1) considered possibly related to treatment; and
• no deaths reported.

Conclusion

Tamoxifen was shown to reduce mutant allele burden in a subset of MPN patients who could be identified by hematopoietic stem cell transcriptomic signature before treatment. The primary endpoint (≥50% decrease in mutant allele burden in peripheral blood at 24 weeks) of this phase II study was met and observed in ≥3 patients. These findings advocate for future clinical studies to test the effectiveness of other selective estrogen receptor modulators in MPN, specifically the Janus kinase 2-signaling pathway.