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PD-1 inhibition in advanced myeloproliferative neoplasms

التفاصيل البيبلوغرافية
العنوان: PD-1 inhibition in advanced myeloproliferative neoplasms
المؤلفون: Hobbs, Gabriela, Bozkus, Cansu Cimen, Moshier, Erin, Dougherty, Mikaela, Bar-Natan, Michal, Sandy, Lonette, Johnson, Kathryn, Foster, Julia Elise, Som, Tina, Macrae, Molly, Marble, Hetal, Salama, Mohamed, Jamal, Siraj M. El, Zubizarreta, Nicole, Wadleigh, Martha, Stone, Richard, Bhardwaj, Nina, Iancu-Rubin, Camelia, Mascarenhas, John
المصدر: Blood Advances; 20210101, Issue: Preprints
مستخلص: Myelofibrosis (MF) is a clonal stem cell neoplasm characterized by abnormal JAK-STAT signaling, chronic inflammation, cytopenias and risk of transformation to acute leukemia. Despite improvements in the therapeutic options for MF patients, allogeneic hematopoietic stem cell transplantation remains the only curative treatment. We previously demonstrated multiple immunosuppressive mechanisms in MF patients, including elevated PD1 expression on T cells compared to healthy controls. Therefore, we conducted a multicenter, open-label, phase 2, single-arm study of pembrolizumab in patients with DIPSS intermediate 2 or greater primary, post-essential thrombocythemia or post-polycythemia vera myelofibrosis that were ineligible for or were previously treated with ruxolitinib (NCT03065400). The study followed a Simon two-stage design, and enrolled a total of 10 patients, 5 of which had JAK2V617 mutation, 2 had CALR mutation and 6 patients had additional mutations. Most patients were previously treated with ruxolitinib. Pembrolizumab treatment was well tolerated but there were no objective clinical responses and thus, the study closed after completion of the first stage. However, immune profiling by flow cytometry, TCR sequencing and plasma proteomics demonstrated changes in the immune milieu of patients suggesting improved T cell responses, which can potentially favor antitumor immunity. The fact that these changes were not reflected in a clinical response strongly suggest that combination immunotherapeutic approaches rather than monotherapy may be necessary to reverse the multifactorial mechanisms of immune suppression in MPN. The study is registered at http://www.clinicaltrials.govas NCT03065400.
قاعدة البيانات: Supplemental Index
الوصف
تدمد:24739529
24739537
DOI:10.1182/bloodadvances.2021005491