PD-1 inhibition in advanced myeloproliferative neoplasms

Abstract

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.gov as NCT03065400.

Essential thrombocythaemia progression to the fibrotic phase is associated with a decrease in JAK2 and PDL1 levels

“…The results of our study can explain, at least in part, the lack of efficacy (clinical or bone marrow pathologic response) of the pembrolizumab treatment in patients with advanced primary, post-ET-MF, and post-PV myelofibrosis [88] and shed more light on the relationship between the types of driver mutations, the PD-L1 expression, and the ET progression to the fibrotic phase.…”

An arginase1- and PD-L1-derived peptide-based vaccine for myeloproliferative neoplasms: A first-in-man clinical trial

“…Otherwise, it will be necessary to combine the vaccines used in the present trial with other agents like an immune-checkpoint inhibitor. To date, treatments with the PD-1 checkpoint inhibitor, Pembrolizumab, have been unsuccessful in patients with MPN (40). However, a case study of a 71-year-old man with ET treated with the PD-1 checkpoint inhibitor, pembrolizumab, for a PD-L1-positive lung adenocarcinoma reported a decrease in elevated platelet counts and a dramatic decrease in the JAK2V617F allele burden after 17 months of pembrolizumab treatment (41).…”

Myelofibrosis treatment history and future prospects

“…The author read and approved the final manuscript. Imetelstat II [31] Pembrolizumab II [32] Nivolumab II [33] Sotatercept II [34]…”

“…Immunological profiling using flow cytometry, T-cell receptor sequencing, and plasma proteomics, on the other hand, revealed alterations in the immune microenvironment of patients, indicating enhanced T-cell responses that may support antitumor immunity. The lack of a therapeutic outcome to these modifications implies that, rather than monotherapy, combined immunotherapeutic treatments may be required to overcome the multiple causes of immune suppression in myeloproliferative neoplasms [32].…”