Macro-Quest

In this issue of Blood, Paiva et al provide important information on the cell of origin in Waldenström macroglobulinemia (WM), a longstanding puzzle due to conflicting and incomplete data.¹ 

WM is not Hodgkin lymphoma. Both are eponymous diseases that carry the name of the physician who initially described them. In both, there has been longstanding confusion about the cell of origin, but the similarity mostly stops there. In Hodgkin lymphoma, the finding that malignant Reed-Sternberg cells originate from B cells was not established until the 1990s, with the use of single cell analysis.²  Until then, we were not fully sure if the malignancy arose from B cells, T cells, or the monocyte lineage. In WM, we have had no such problem: the fact that the malignant cells were lymphoid in origin and secreted immunoglobulin has been known almost from the outset. However, the problem in WM has been more subtle and revolves around the precise nature of the B-cell lineage differentiation stage (from a pregerminal center B cell up to fully differentiated plasma cells) that is responsible for the malignancy. Paiva et al clearly show that WM, and its precursors immunoglobulin-M (IgM) monoclonal gammopathy of undetermined significance (MGUS), and smoldering WM, arise from CD25⁺CD22^+low activated B lymphocytes based on sensitive multiparametric flow cytometry and gene expression profiling (GEP) studies.¹  They also confirm that the clonal cells in WM are almost uniformly negative for CD5, CD10, CD11c, and CD103. These results are not just of historic and biologic relevance, but also provide a unique immunophenotype that can be used to discriminate patients with WM from other related B-cell lymphoproliferative disorders. This would be of particular value in reaching the correct diagnosis in WM patients with nonmutated MYD88, as well as those with other related (non-WM) B-cell disorders that harbor the MYD88 mutation.

Most patients with WM have a recurrent somatic mutation, L265P, involving the MYD88 gene.^3,4  Subsequent studies have found that this mutation is also present in the precursor stages of the disease, including IgM MGUS, suggesting that MYD88 L265P is an early event and that additional cytogenetic changes are necessary for the evolution of the malignancy.⁵  In line with this, Paiva et al demonstrate that certain cytogenetic copy number abnormalities including +4, +12, del(6q23.3-6q25.3), and +18q21.1 are more prevalent in patients with malignant transformation to WM and need further study. It is, however, interesting that as in myeloma, none of these changes resulted in a major shift in GEP. Although larger series of patients are needed to confirm these findings, they found no significant differences on GEP between the clonal cells of WM and IgM MGUS. In contrast, clonal cells of WM and IgM MGUS displayed several deregulated genes in comparison with normal resting B cells, and these changes involved many signaling pathways. Some of these genes and signaling pathways should be explored to determine whether it is possible to therapeutically revert the WM clone into a resting phenotype.

Most importantly, the paper also clarifies semantics related to WM that have been the source of much confusion and controversy for a long time. Some guidelines have suggested that any level of infiltration of the bone marrow with clonal WM cells with any level of IgM monoclonal protein be termed WM.⁶  Such a definition would make WM the most common malignancy in the world because an IgM MGUS is present in ∼1% of the general population over the age of 50, and as the authors show, infiltration of the bone marrow by clonal cells can be demonstrated in most cases of IgM MGUS using sensitive studies. Clonal cells detected in IgM MGUS are indistinguishable from the clonal cells in WM using current techniques in a reliable manner. We know that patients with IgM MGUS defined as <10% clonal bone marrow involvement and no end-organ damage have a low risk of progression to symptomatic WM (1.5%/year)^7,8  and have an overall survival similar to or even better than an age-matched general population!⁹  Thus, I agree with the authors that the level of clonal infiltration (≥10% vs <10%) rather that the presence or absence of such infiltration be used to distinguish WM from IgM MGUS. In fact, according to the present study, there is considerable overlap between the phenotypic characteristics of clonal cells from benign vs malignant disease stages, and accordingly, the transition from one to the other is mostly related to the level of clonal infiltration. The IgM MGUS disease definition⁷  prevents us from applying the label of malignancy to people, most of whom will never develop any signs or symptoms of WM.

Even in the presence of ≥10% clonal infiltration of the bone marrow, patients without end-organ damage can remain stable without therapy for extended periods of time.¹⁰  Such patients, termed smoldering WM, occupy a clinical stage in between IgM MGUS and WM. The study by Paiva et al confirms that except for some secondary cytogenetic events, there are little differences between the clonal cells of these 3 entities, even though the clinical phenotype is remarkably different.

Jan Waldenström did not know about IgM when he first described WM. Today, 70 years later, we know plenty about IgM, but the nature and definition of the disease continue to evolve.