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T.I. Mughal et al.
Grootens and colleagues identified KIT 816V in early SM stem cells and progenitors, suggesting that this biomarker may not be restricted to the mast cell lineage.37 In the same study it was observed that the mutation frequency was 100% in mature CD45RA+ mast cells.
Screening for clonal hematopoiesis of indeterminate potential
NGS-based genetic analysis of large unselected popula- tions assessing acquisition of somatic mutations has provid- ed evidence of age-related clonal expansion of recurrent mutations in known oncogenes in hematopoietic stem and progenitor cells in the absence of overt hematologic malig- nancies, a condition termed clonal hematopoiesis.38 The somatic mutations that define clonal hematopoiesis tend to be similar to those found in hematologic malignancies, such as ASXL1, DNMT3A, RUNX1, JAK2, TET2, SF3B1 and oth- ers, with a variant allele frequency >2% in subjects without cytopenias or a history of a myeloid neoplasm. The muta- tions are typically present in circulating granulocytes, monocytes, and natural killer cells; they can also affect B cells and, rarely, T cells. Clonal hematopoiesis is considered to represent the early steps of leukemogenesis and is asso- ciated with an increase in the risk of myeloid and lymphoid malignancies of 0.5% to 1.0% per year.39 Evidence from ret- rospective case-control studies supports the role of clonal hematopoiesis in therapy-related myeloid neoplasms, too.40 The mutations can also be associated with acquired drug resistance. Somewhat surprisingly, clonal hematopoiesis is also associated with a pro-inflammatory state and an increased risk of various non-hematologic diseases, in par- ticular cardiovascular disease, attributed to genes that are involved in regulating inflammation and accelerating ather- osclerosis.41,42 Interestingly, Hameisterr and colleagues recently investigated whether clonal hematopoiesis might affect the course of COVID-19 in hospitalized older patients who had tested positive for SARS-CoV-2 infection and found no significant association.43
Although it is recognized that people with clonal hematopoiesis develop MPN at a higher rate than those without mutations, the precise impact of clonal hematopoiesis on the prognosis and treatment of MPN is an enigma.44 An important challenge is, therefore, to assess the clinical relevance of clonal hematopoiesis at the time of diagnosis of MPN and assess its potential prognostic value, in particular in the transformation to acute leukemia and in treatment resistance. The presence of clonal hematopoiesis may also affect the ‘real-world’ situation in people with CML, MF and SM who have been treated ‘successfully’, including those who have undergone allogeneic stem cell transplantation, when such mutations could be donor- derived and influence the assessment of measurable resid- ual disease.45 Genomic studies, in particular those involving single-cell sequencing, are being increasingly integrated into the investigation of MPN at diagnosis and transformation, which also raises the question of which genes should ideal- ly be included in the NGS panel. Furthermore, we are beginning to fathom the complexity of the cancer tissue ecosystem and how this is affected by different features, such as the cells’ metabolism and how it co-opts normal genes, stromal and immune cells within the microenviron- ment, among other variables. In this regards the recent work of Van Etten, Krause and others on the specific, tar-
getable interactions with the microenvironment in people with imatinib-resistant CML is important.46 Despite the therapeutic advances in CML, MF and SM, the outlook for people whose disease transforms remains bleak and high- lights the need for suitable prognostic scores to identify those at high risk of progression who may benefit from more intensive initial treatments, including allogeneic stem cell transplantation.
Future prospects
We have clearly made significant progress by examining MPN through genetics and physiology, by the unprecedent- ed application of ‘-omics’ technology, ultrasensitive sequencing technology and single-cell genomics. Such approaches have arguably enhanced our understanding of chronic myeloproliferative malignancies, and the character- ization of the underlying intratumor heterogeneity and the ability of the neoplastic clone to evolve and adapt has been recognized as a principal challenge for targeted treatments and immunotherapies.47 The different genetic tests in MPN clinics have undoubtedly improved our ability to monitor patients effectively and have refined diagnostic risk stratifi- cation.48 For CML patients, they also enhance the probabil- ity of TKI cessation and achieving TFR; for patients with MF and SM, they are complementary to the World Health Organization 2016 diagnostic criteria and help in navigating treatment decisions. These tests also allow for a better selection of targeted agents to be tested in subgroups with variant somatic mutations. Nevertheless, much work remains. For example, we have little understanding of the cell-intrinsic and -extrinsic mechanisms underpinning the transformation of MPN into acute leukemia, or the mecha- nisms of resistance to the newer inhibitors, to mention a few.49 The emerging picture is complex but has created a platform upon which to build novel therapeutic approach- es.
Disclosures
DJDA has provided consultancy/scientific advisory board servic- es for Amgen, Autolos, Agios, Blueprint, Forty-Seven, Incyte, Jazz, Novartis, Pfizer, Shire, and Takeda and has received research funding from Abbvie, Glycomimetics, Novartis and Blueprint Pharmaceuticals. TIM has stocks or employment connections with Stemline; and receives royalties from Oxford University Press and Informa. BP has provided consultancy services for Novartis and Constellation. JPR has been part of scientific advisory boards for Novartis, Amgen, BMS, and Jazz Pharmaceuticals; and per- formed laboratory contract work for Novartis. GS has no relevant disclosures to make. RAVE has provided consultancy services for Novartis.
Contributions
TIM, BP and JPR wrote the draft versions of the manuscript, without any writing assistance provided by a third party. All authors edited and approved the final version of the manuscript.
Acknowledgments
The authors would like to thank Dr Alpa Parmar and partici- pants of the XIV Post ASH MPN workshop for their assistance.
Funding
The authors would like to thank Alpine Oncology Foundation for funding.
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