634. Myeloproliferative Syndromes: Clinical: Translational Science in MPN— Hitting the Mark

Watch Session

342 Effects of Tamoxifen on the Mutant Allele Burden and Disease Course in Patients with Myeloproliferative Neoplasms – Results of the Tamarin Study

Claire Harrison, Joanna E Baxter, Rebecca H. Boucher, et al.

Authors Conclusion from the Abstract: These results demonstrate the safety and activity of tamoxifen in reducing mutant allele burden in a subset of MPN patients who could be prospectively identified based on their transcriptomic signature at baseline. Tamoxifen can induce apoptosis of human JAK2V617F or CALR mutated HSPCs through metabolic and transcriptional effects. These results advocate for future studies to test the effects of SERMs in MPN with careful consideration of thrombotic risk.

Clemence Marcault, Lin-Pierre Zhao, Rafael Daltro De Oliveira, et al.

Authors Conclusion from the Abstract: In this retrospective study we show that presence of NFE2 mutations with a VAF ≥5% is independently associated with an increased risk of leukemic transformation and shorter overall survival. These findings are in line with recently reported animal models and suggest that NFE2 mutations screening should be routinely performed in MPN patients.

Franco Castillo Tokumori, Chetasi Talati, Najla E. Al Ali, et al.

Authors Conclusion from the Abstract: Splicing mutations in MF have unique phenotypic and prognostic correlations. While SRSF2 mutations appear detrimental, SF3B1 mutations correlate with favorable outcomes. While U2AF1 and SRSF2 mutations are considered high-risk in MF, the impact appears driven by cytopenias in the former and leukemic transformation in the latter. This may hold relevance when considering therapeutic approaches in these patients.

Jason Gotlib, Deepti H. Radia, Tracy I. George, et al.

Authors Conclusion from the Abstract: In the phase I EXPLORER study, response assessment in AdvSM using PPR criteria increases the evaluable population, significantly correlates with OS, and should be explored as a potential primary endpoint for future trials.

John Mascarenhas, Rami S. Komrokji, Michele Cavo, et al.

Authors Conclusion from the Abstract: Clinical responses to imetelstat treatment were observed regardless of baseline cytogenetic status, and a subset of pts achieved ≥50% reduction in cytogenetically abnormal clones. Significant dose-dependent reductions of mutation burden by imetelstat were noted and correlated with improved overall clinical benefits including higher rates of spleen and symptom responses, bone marrow fibrosis improvement, and prolonged OS. Together with the clinical data that suggest improvement in median OS in these pts, the data presented here further demonstrate that imetelstat has disease-modifying activity by targeting malignant cells, as evidenced by depletion of cytogenetically abnormal clones and reduction in mutation burden. These results will be confirmed in the planned Phase 3 study in refractory MF.

John Mascarenhas, Rami Komrokji, Michele Cavo, et al.

Authors Conclusion from the Abstract: Dose-dependent inhibition of telomerase target, evaluated by TA and hTERT reduction, was demonstrated in R/R MF pts treated with imetelstat, and this on-target activity correlated with clinical responses and longer OS. Improved clinical outcomes were noted in pts with shorter telomeres and high hTERT expression. These data are consistent with telomere biology in cancer cells and provide evidence for the on-target mechanism of action of imetelstat through telomerase inhibition.