“What's in a name?” Shakespeare's timeless inquiry begins, as he famously asked us to ponder the concept of nomenclature for nomenclature's sake. Well, the answer it turns out, in 2016 and beyond, is actually quite a lot in our field.
That's because authors on behalf of the World Health Organization (WHO) published a high-impact 2016 revision of the extremely helpful classification of WHO myeloid neoplasms and acute leukemias from 2008 (Blood 2009;114:937-951, Blood 2016;127:2391-2405). Led by Arber and colleagues, this document outlines a roadmap for a way to rationally approach a constantly shifting landscape in the complex area of diagnosis and nomenclature of the myeloid malignancies.
In the 65 years that have elapsed from the time of the seminal findings of William Dameshek to the present day WHO 2016 revision, the field of myeloproliferative neoplasms (MPNs) has truly experienced an amazing amount of research and growth (Blood 1951;6:372-375). With our ever-growing emphasis on biological discoveries, and the novel, advanced techniques that are allowing for these discoveries, this has begun to make a positive impact on the way we diagnosis, prognosticate, and even treat our patients (ASCO Educational Handbook 2015;35:139-145).
Therefore, the current re-classification is important for all hematologists/oncologists, and it carries with it several practice-changing motifs that I want to highlight for you. A few of the items from the paper really caught my immediate attention; there are several key changes that have been put forward.
It is worth noting that this unique entity has now been given its own separate category outside of the MPNs. This is owing to an exponential increase in research in this area that has really delineated that mastocytosis has a distinct patho-biological disease state from the other MPNs and the other myeloid neoplasms. On the clinical side, this has indeed been reflected by a rising number of new findings with regards to novel pathways, identification of mutations, and clinical trials specifically including patients with mastocytosis (N Engl J Med 2016;374:2530-2541, Curr Hematol Malig Rep 2015;10:351-361).
Creation of “Pre-Fibrotic Myelofibrosis”
Another major change in the MPN category is the establishment now of a distinct “in-between” category, known as pre-fibrotic myelofibrosis (MF), distinguishing this category from essential thrombocytosis (ET) and overt MF, based on absence of reticulin fibrosis and differences in other elements of the bone marrow evaluation. This entity will need to be further fleshed out over time, by pathologists and clinicians alike, and will likely be the subject of many debates and discussions in the years to come (Blood 2017;129:680-692).
The central questions in this new category will include:
1. Can this complex entity be reliably recognized with accuracy and precision, with minimal inter-observer variation?
2. Will this entity truly prove to have distinct prognostic (and even therapeutic) implications for our patients?
The answers here remain to be seen and eagerly awaited; notably, many groups have already begun working prospectively on answering these and other questions for this newly established field.
Polycythemia Vera Hemoglobin Cutoff
Yet another important change was made in the MPN category. After years of discussions and studies, ultimately the WHO 2016 report produced a major change in hemoglobin cutoff for the diagnosis of polycythemia vera (PV) (N Engl J Med 2013;368:22-33). This included bringing the hemoglobin level required for diagnosis down from 2008 (18.5 g/dL in men down to 16.5 g/dL; and from 16.5 g/dL for women, down to 16 g/dL) (Blood 2016;127:2391-2405).
Additionally, parameters for hematocrit and red cell mass are also now included as part of the major criteria for diagnosis. These changes were made, in part, due to the recognition of entities such as “masked PV,” which lead to presentation of PV, in both men and women, with lower Hb cutoffs than recognized by the 2008 guidelines, but still represented cases of true PV (Hematology Am Soc Hematol Educ Program 2016;2016:534-542).
Discovery & Availability of Calreticulin (CALR) Testing
Subsequent to the JAK2 V617F and MPL mutation elucidations, a third major driver mutation has been discovered to be of utmost importance to the MPN field. In 2013, two simultaneous reports found that mutations in CALR constituted the second most common recurring driver mutation, after only JAK2, in patients with ET and MF (N Engl J Med 2013;369:2379-2390, N Engl J Med 2013;369:2391-2405).
Ever since, augmented by the rapid adaptation of standardized pathologic testing for this mutation, CALR has correctly become a staple of diagnostic standard procedure in the MPN field; furthermore, there have been several studies showing possible prognostic implications for this mutation, making the finding of this new mutation an important practice-changing item of which all clinicians should be aware (Blood 2017;129:680-692, Blood 2014;123(10):1544-1551).
These aspects are just some of the many pearls of information from the WHO 2016 reclassification. In this article, I focused on some of the changes impacting the field of MPNs. In reference to the difficulties of always trying to find a “one best way” in medicine, Hartzbrand and Groopman once eloquently wrote “good thinking takes time” (N Engl J Med 2016;374:106-108).
When you have a moment, take some time to read over and think about the new categorizations, and let's start to envision together how this will start to change our practice. One of the major trends in our field this year will indeed be attempting to digest, absorb, discuss, and debate, and begin to implement into our practices some of the new paradigms enumerated in this reclassification, and my hope is this article gets you started thinking about these changes.
NAVEEN PEMMARAJU, MD, is Assistant Professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston.