Clonal disorders of clinical significance. A concept with important therapeutic implications

Several diseases result from the biological activity of molecules synthesized by cells in various parts of the body. For example, when the cells that synthesize these molecules are those of a solid cancer, leading to various manifestations at distant sites, without a direct link to the tumour, it is referred to as a paraneoplastic syndrome.

Such distant manifestations can also occur with plasma cell dyscrasias. Plasma cells synthesize immunoglobulins. A clonal proliferation of plasma cells synthesizes monoclonal immunoglobulins, either as part of a well-defined hemopathy such as myeloma (IgG, IgA), Waldenström's disease (IgM) or in the context of a monoclonal gammopathy of undetermined significance (MGUS). In 2006, Merlini and Stone introduced the term ‘dangerous small B-cell clones’ stating that ‘even a small clone, as seen in MGUS, may synthesize a noxious monoclonal protein that can be responsible for devastating systemic organ damage dominating the clinical presentation, altering the natural history, and determining the prognosis’.¹ This publication paved the way for redefining some cases of MGUS as monoclonal gammopathy of renal significance,² monoclonal gammopathy of cutaneous significance³ or the generic term monoclonal gammopathy of clinical significance, which includes neurologic to thrombotic manifestations.

The article by Theves et al.⁴ published in this issue of the Journal perfectly illustrates this concept. The authors show that targeting plasma cells in patients with scleromyxedema can induce durable responses. Scleromyxedema is a mucinosis characterized by a generalized papular and sclerodermoid eruption that usually occurs in association with a monoclonal gammopathy. It can be an extremely serious disease due to dermato-neuro syndrome, which can be fatal, or because of severe cardiac involvement. Its treatment is challenging. The authors demonstrate that targeting plasma cells yields excellent therapeutic results, supporting the fact that scleromyxedema belongs nosologically to the group of monoclonal gammopathy of cutaneous/clinical significance.

I now wish to extend this concept to all clonal pathologies and introduce the concept of clonal disorders of clinical significance. Merlini referred to ‘dangerous small B clones’, but there are also dangerous small T clones. We followed up a patient with hypereosinophilic syndrome. She had many manifestations related to hypereosinophilia, including urticarial plaques, widespread red and scaly itchy lesions, enlarged lymph nodes, and a deterioration of her general condition. Treatments targeting hypereosinophilia, such as steroids, interferon or mepolizumab, did not control the clinical manifestations. She had a CD3− CD4+ T-cell clone. We postulated that this T-cell clone was responsible for the secretion of cytokines, such as IL-5, which caused eosinophilia and the clinical manifestations. When we targeted this clone with mogamulizumab, a complete response was achieved (D. Lipsker, personal observation).

Because it is outside the scope of this commentary, I will briefly mention that in the coming years, many inflammatory disorders, similar to the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome,⁵ will be shown to be the consequence of clonal haematopoiesis of clinical significance (still referred to as clonal haematopoiesis of indeterminate potential). This group of disorders also fits perfectly into the general concept of clonal disorders of clinical significance. Treating the underlying clone will be much more effective than treating the inflammatory consequences.

The concept of clonal disorders of clinical significance is not merely a play on words. Conceptualizing a small clone, which in itself as a ‘tumour’ does not cause harm, but which causes harm by producing deleterious molecules that have significant clinical consequences, opens up new therapeutic perspectives. In the example of the patient with the hypereosinophilic syndrome, the classic therapeutic approach was treating hypereosinophilia, rather than its cause, the clone, which can sometimes be very minor. Thanks to enormous progress over the last 20 years, during which numerous new treatments have emerged that allow for the specific targeting of cell types or cytokines, more rational treatment strategies have become possible. We must acquire the reflex of considering a clonal proliferation, which can be barely detectable by current means of investigations, as the source of a broad clinical picture. This represents a shift in the paradigm. Clinicians, particularly dermatologists, should therefore familiarize themselves with the concept of clonal disorders of clinical significance, which opens up new therapeutic perspectives.

No conflict of interest.