In Response to Lymphohematopoietic Clones

In the July/August 2022 issue of The Hematologist, Dr. Marshall Lichtman (Lymphohematopoietic Clones: Are They of Unknown Significance, Indeterminate Potential, or Indeterminate Progression? The Hematologist. 2022;19[4]:14) critiques the term “clonal hematopoiesis of indeterminate potential” (CHIP) — a name we proposed in 2014 to describe a newly discovered subtype of aging-associated somatic mosaicism in hematopoietic cells, and a term that was recently incorporated into the fifth (2022) edition of the World Health Organization Classification of Haematolymphoid Tumors, along with another widely used label, clonal cytopenias of undetermined significance (CCUS).^1,2  Dr Lichtman agrees that CHIP is a useful term, but states, “The choice of the suffix ‘indeterminate potential’ was perhaps just off point. The potential [of these clones] also had been determined. Their time of progression could not be. Thus ‘indeterminate progression’ is a more precise and relevant term.” He also endorses the term monoclonal gammopathy of indeterminate progression (M-GIP) for a parallel pre-malignant clonal state in plasma cells that has been recognized for more than 60 years, and has been known as monoclonal gammopathy of undetermined significance (MGUS) since the classic studies of Dr. Robert Kyle in the 1970s.^3,4 

Thoughtful re-evaluation of widely used terminology in light of new discoveries is always welcome. However, we believe that “potential” remains a more useful descriptor of the possible behaviors of this form of somatic mosaicism than “progression.” A risk of clonal evolution and progression to an overt myeloid or lymphoid neoplasm is only one association with CHIP. Already in 2014, it was clear that clonal hematopoiesis is associated with an increased risk of cardiovascular events and with elevated overall mortality that cannot be explained solely by hematologic neoplasia; the inflammation-based pathophysiology of this association and interaction of clonal cells with vascular endothelium has become clearer since then.^5,6  Increased risk for or severity of a broad range of other non-neoplastic conditions has been linked to the presence of clonal hematopoiesis, including chronic obstructive pulmonary disease, gout, chronic liver disease, and graft-versus-host disease after allogeneic hematopoietic cell transplantation.^7-10  Conversely, CHIP may be protective against dementia through mechanisms that are as yet unclear but that may involve replacement of microglial supporting cells in the central nervous system that diminish with aging.¹¹ 

For these types of events, substituting “progression” in CHIP would be misleading, as the underlying clonal state itself usually remains unchanged. Similar considerations apply to MGUS versus M-GIP: nephropathy, neuropathy, immunologic dysregulation, or other complications can develop in the absence of clonal progression to myeloma.

In contrast to progression, which implies an intrinsic change in the underlying clonal state, the term “potential” highlights more broadly the capacity of CHIP to either develop into a neoplasm in the future or alternatively, to act on other tissues without itself evolving — a unique property of circulating blood cells compared to somatic mosaicism in other tissues. The word potential is derived from the Latin potentia, an adjective meaning power or ability. There is no question that some forms of clonal hematopoiesis are a powerful risk factor for cardiovascular events and other nonhematologic conditions, in addition to possessing the ability to progress to neoplasia. More work needs to be done to define which specific mutations, clonal architectures, and interacting features such as germline genetics are associated with greater or lesser risk. For these reasons, we favor retaining the term “potential” rather than “progression” within the CHIP designation.

Reply: Drs. Steensma, Bejar, Jaiswal, Sekeres, Hasserjian, and Ebert write that CHIP is their preferred terminology. They, not surprisingly, give understandable reasons for their preference. “Clonal hematopoiesis of indeterminate progression,” retaining the acronym CHIP, may be more to the point from the patient’s perspective. In the case of CHIP, either “potential” or “progression” could incorporate the dual concerns of clonal evolution to a more threatening neoplasm and the association with coincidental inflammatory disease, for example. Moreover, we are rapidly unveiling its potential, although, perhaps, not yet the full pathogenesis of the coincidental disorders. If the patient asked their physician: “What is the potential of this diagnosis?” the physician can provide a fulsome explanation to the patient. If conversely the patient asked, “When would the clone progress to that potential outcome?” one would have to say that is indeterminate. More to my point, the prepositional phrase “of indeterminate progression” could be used for several incipient neoplasms, providing unity and focus. We agree that further study to understand the links that result in the two pathogenetic processes, neoplasia and inflammation in the case of CHIP, is an important goal. The progression to a potentially lethal neoplasm was my focus. Even though the lifetime risks are low, they are not inconsequential. The ability to interdict a clone in order to prevent its progression is another worthy goal. These aforementioned etymological distinctions are less important than a more central matter. 1) Unify similar pathogenetic processes with comparable nomenclature for the sake of enhanced understanding. Use monoclonal gammopathy of indeterminate progression with the acronym M-GIP. Refer to clonal cytopenia of unknown significance as clonal cytopenia of indeterminate progression with the acronym C-CIP, if an acronym is unavoidable. Why should these similar pathogenetic processes have inapt designations? This would bring them into the fold with CHIP. By unifying them, one provides insight. 2) We should not indicate to a patient that we do not know the significance or potential of their diagnosis when we do. It is implicit that there may always be more to learn. Read the back and forth in the exchange that follows as two medical groups try to outdo the other in describing the significance of monoclonal gammopathy of unknown significance. This excerpt is from an editorial written a decade ago.

“The term “monoclonal gammopathy of unknown significance (MGUS)” belies two facts: (1) it is one of numerous non-progressive monoclonal (neoplastic) disorders with a propensity to undergo clonal evolution to a malignant neoplasm and, thus, it represents a known (not unknown) spectrum of neoplastic diseases; and, (2) we have a great deal of information on its significance.

Thus, I had to chuckle when in an exchange of letters in the journal Blood the authors stated “While this association is expected, the findings are important and further strengthen the biologic significance of monoclonal gammopathy of unknown significance”; and, “Although, for the individual patient, it is currently not possible to predict whether the underlying monoclonal gammopathy of unknown significance will remain benign or transform to MM [multiple myeloma], from a population standpoint the significance of monoclonal gammopathy of unknown significance has been well characterized”¹²  The citations to the exchange on the “well characterized significance of unknown significance” are in reference 12. The dialogue states categorically what is unknown is the time of progression. We are a scientific discipline. Language is important, notably to our patients. Does anyone tell a patient that he or she has a significant disorder of unknown significance? I hope not.

For reasons not evident to me, hematologists add prepositional phrases to indolent neoplasms: of unknown significance, of (insert the relevant organ) significance, of indeterminate potential, of oncogenic potential. I, reluctantly, have joined the cause with “of indeterminate progression” but only for clarity. Such designations are not a feature of indolent neoplasms of other tissues: adenomas of many tissues, glioma, fibroma, leiomyoma and innumerable others. Some indolent neoplasms also have extraneous deleterious effects, such as the pheochromocytoma and the idiosyncratic effect of a monoclonal protein, as in the induction of the TEMPI syndrome or acquired von Willebrand disease. Students of oncogenesis have learned of their significance and potential over periods of study and explain that to their patients. Hematologists could do the same. In my chapter on the topic, I use the designation essential monoclonal gammopathy, but could use monoclonal gammopathy of indeterminate progression, as I indicated therein.¹³  Moreover, there are more than 20 very uncommon idiosyncratic events resulting from a particular monoclonal immunoglobulin.¹  Does one want to say “of (fill in the tissue affected) significance” for each? Of corneal significance? Monoclonal immunoglobulin crystalline keratopathy can cause blindness.¹⁴  We know these uncommon or rare manifestations to be an intrinsic feature of the disease, as we know of the varied consequences of type 1 diabetes mellitus or Gaucher disease. The former has the potential to incur profound secondary effects on the vasculature of various organs, the eye, the limbs, the heart, and the brain, and the latter has strong, probably causal, relationships to neoplasia, monoclonal gammopathy, myeloma, and more, intrinsic to that disease. These complexities are wrapped in the simple eponymic designation, Gaucher disease.

I commend Drs. Steensma, Bejar, Jaiswal, Lindsley, Sekeres, Hasserjian, and Ebert, first for their impactful paper,¹  as I did previously,¹⁵  and second, for not using the designation “of unknown significance” to describe clonal hematopoiesis. There is no shame in improving medical terminology after nearly a half-century (or after any period). It is a sign of progress, not a criticism, as I tried to indicate in my commentary. I hope that this exchange will heighten an interest in bringing clarity to the designation of hematopoietic and lymphopoietic clones, each, in occasional cases, the larval stage of a more advanced neoplasm; that is their potential. We just do not have a means to know with certainty whether or when that progression will occur.

— Marshall A. Lichtman, MD, Professor Emeritus of Medicine (Hematology) and of Biochemistry and Biophysics, James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY