Illuminating novel biological aspects and potential new therapeutic approaches for chronic myeloproliferative malignancies

Abstract

This review reflects the presentations and discussion at the 14th post-American Society of Hematology (ASH) International Workshop on Chronic Myeloproliferative Malignancies, which took place on the December 10 and 11, 2019, immediately after the 61st ASH Annual Meeting in Orlando, Florida. Rather than present a resume of the proceedings, we address some of the topical translational science research and clinically relevant topics in detail. We consider how recent studies using single-cell genomics and other molecular methods reveal novel aspects of hematopoiesis which in turn raise the possibility of new therapeutic approaches for patients with myeloproliferative neoplasms (MPNs). We discuss how alternative therapies could benefit patients with chronic myeloid leukemia who develop BCR-ABL1 mutant subclones following ABL1-tyrosine kinase inhibitor therapy. In MPNs, we focus on efforts beyond JAK-STAT and the merits of integrating activin receptor ligand traps, interferon-α, and allografting in the current treatment algorithm for patients with myelofibrosis.

Analysis of the Clinical Significance and Safety of Interferon in the Treatment of Chronic Myeloproliferative Tumors

“…Li et al [ 14 ] found that the gene load of JAK2V617F mutation in patients with MPN was closely related to the severity and duration of the disease. Zhang et al [ 15 ] found that IFN- α specifically blocked the proliferation advantage of JAK2V617F mutant hematopoietic stem cells in mice, thereby preventing the development of MPN and even achieving eradication [ 16 ]. Clinical research has reported that some patients with MPN treated with IFN achieved complete hematologic and molecular biological remission [ 17 ].…”

Single-cell RNA sequencing to track novel perspectives in HSC heterogeneity

“…Unlike Tyrosine Kinase Inhibitors (TKI) in CML, survival of patients with MF is not substantially improved by currently available JAK inhibition therapies since the possibility of appearance of unrelated clones over time [ 100 ]. Therefore, a major focus of drug developments is identifying novel targets beyond JAK inhibitors [ 101 ]. In this regard, a novel single-cell ‘‘multi-omics’’ method, including scRNA-seq, targeted single-cell mutational analysis with simultaneous scRNA-seq (TARGET-seq) and single-cell proteomics, has advanced ultimate reconstruction of tumor phylogenetic trees.…”

Perspective: Pivotal translational hematology and therapeutic insights in chronic myeloid hematopoietic stem cell malignancies

“…Momelitinib and pacritinib, also type I JAK2 inhibitors, are in late stage development and anticipated to be licensed soon, in particular for patients with anemia and thrombocytopenia. 15,16 Indeed, pacritinib was licensed on 28th February 2022 by the US Food and Drug Administration (FDA) for the treatment of adult patients diagnosed with intermediate or highrisk MF with baseline platelets (50 � 10 9 /L). Momelitinib mitigates anemia by inhibiting the activin A receptor and decreasing hepcidin production; pacritinib has a nonmyelosuppressive profile and appears suitable for thrombocytopenic patients, in which the drug is currently being tested in a randomized, controlled, phase 3 study (PACIFICA).…”

“…Preclinical studies, however, suggest cross‐resistance among type I JAK2 inhibitors. Momelitinib and pacritinib, also type I JAK2 inhibitors, are in late stage development and anticipated to be licensed soon, in particular for patients with anemia and thrombocytopenia 15,16 . Indeed, pacritinib was licensed on 28th February 2022 by the US Food and Drug Administration (FDA) for the treatment of adult patients diagnosed with intermediate or high‐risk MF with baseline platelets (50 × 10 9 /L).…”