Advances in chronic myelomonocytic leukemia and future prospects: Lessons learned from precision genomics

Abstract

In the latest World Health Organization classification of myeloid neoplasms, chronic myelomonocytic leukemia (CMML) exists as a separate entity under the category of myelodysplastic/myeloproliferative (MDS/MPN) overlap syndromes. Outcomes remain uniformly poor with a median overall survival of ~2 years and an inherent risk of transformation into acute myeloid leukemia (15%‐20% over 5 years). Due to unique biologic characteristics such as overlapping features of myelodysplasia and myeloproliferation, and clinical diversity despite relative genomic homogeneity, CMML represents a unique model to study chronic myeloid tumor biology. Recent advances have focused on understanding the role of putative genomic abnormalities, in particular, clonal evolution of pathogenic alterations in genes regulating the epigenome (TET2), chromatin architecture (ASXL1), spliceosome complex (SRSF2, SF3B1), and cell signaling (NRAS, KRAS, CBL, JAK2). Disease prognostication has evolved from purely clinical prognostic models to those incorporating pathogenic gene variants. Therapeutic options in this disease remain dismal with only two agents approved by the United States Food and Drug Administration, namely 5‐azacitidine and decitabine. Allogeneic hematopoietic stem cell transplantation remains the sole curative option in this disease; however, is associated with substantial treatment‐related morbidity and mortality. Future areas of research include opportunities to further improve disease prognostication by employing novel technologies such as machine learning, incorporation of methylation and cytokine signatures, in addition to gene mutations; insights into clonal origins of this disease, and novel therapeutic strategies.

Plasmacytoid Dendritic Cells, a Novel Target in Myeloid Neoplasms

“…The expression of Program Death ligand 1 (PD-L1) by CD34 + CMML cells was reported higher than in AML and MDS and increased during hypomethylating agent treatment associated with poorer survival, suggesting an immune escape mechanism [ 106 ]. Immunosuppression by myeloid-derived suppressive cells has also been suggested in CMML [ 107 ] Moreover, DC nodules, composed mainly of pDCs, have long been known to exist in the BM microenvironment in above 20% of CMML patients [ 108 , 109 ], but their functions are not really known [ 110 ]. Recently, a study highlighted the clonal maturation of pDCs in above 30% of CMML patients, composed of mature pDC nodules with the lin − CD45 + CD123 + CD11c − CD33 − HLA-DR + CD303 + CD304 + phenotype, often associated with RAS pathway mutations and inferior leukemia-free survival (LFS) [ 99 ].…”

How I investigate chronic myelomonocytic leukemia

“…Immune and other cell-based therapies remain largely unexplored in CMML, thus providing opportunities for future novel disease-modifying therapies. 7 In this regard, preliminary data suggest a possible use of anti-CD123 therapy in this disease. 8 However, allogeneic stem cell transplantation still represents the only curative therapy for CMML.…”

“…Cytoreductive therapies (such as hydroxyurea) are instead preferred in case of marked leukocytosis, constitutional symptoms and/or splenomegaly. Immune and other cell‐based therapies remain largely unexplored in CMML, thus providing opportunities for future novel disease‐modifying therapies . In this regard, preliminary data suggest a possible use of anti‐CD123 therapy in this disease .…”

Mouse Models of CMML

“…Of note, such conditions are similar to clonal hematopoiesis of indeterminate potential (CHIP), a phenomenon characterized by the presence of a clonal blood cell population with neoplasm driver mutations in healthy individuals [ 57 ]. Late clonal dominance is suspected to be achieved via the acquisition of mutations in the RAS component pathway, JAK2 , SF3B1 , and RUNX1 [ 31 , 54 , 58 ], resulting in the dysplastic or proliferative subtypes of CMML ( Figure 2 ). This is consistent with data obtained from patients with CMML, where SF3B1 and U2AF1 are associated with the MD-type, while TET2 , SRSF2 , RUNX1 , NRAS , KRAS , and EZH2 are the most frequently detected abnormalities for the MP variant [ 55 , 59 ].…”