Expert Explains WHO Classification Refinements in Hematologic Malignancies

Ahmet Dogan, MD, PhD

Changes are underway in the field of hematologic malignancies, as the World Health Organization (WHO) is publishing a revised classification of tumors of hematopoietic and lymphoid tissues—slated to be released in early 2017.

Within the updated classifications, explains Ahmet Dogan, MD, PhD, are refinements to diagnosis, prognosis, and therapeutic approaches based on important advances in these areas.

“The main aim is to simplify and standardize the classification, not only for contemporary therapy but for future clinical trials so that the different studies could compare results successfully—if they use the same classification,” said Dogan, who spoke on the WHO classification during the 2016 OncLive® State of the Science Summit on Hematologic Malignancies.

In an article published in Blood regarding the upcoming changes, the authors note that the revision “clarifies the diagnosis and management of lesions at the very early stages of lymphomagenesis, refines the diagnostic criteria for some entities, details the expanding genetic/molecular landscape of numerous lymphoid neoplasms and their clinical correlates, and refers to investigations leading to more targeted therapeutic strategies.”¹

OncLive: What did you discuss at this State of the Science Summit?

Dogan, who is chief of Hematopathology Service, Departments of Pathology and Laboratory Medicine at Memorial Sloan Kettering Cancer Center, discusses the updates to the WHO classification and the impact this will have on clinical practice, specifically in the areas of mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and Hodgkin lymphoma.Dogan: There is a new WHO classification that will be published early in 2017. We were following the developments at the 2016 ASH Annual Meeting in the context of that new classification.

What are the details of these refinements?

The highlights of the classification include a number of changes or refinements of existing entities. These include the definition of so-called monoclonal B-cell lymphocytosis (MBL), the definition of indolent variant of MCL, refinements to the DLBCL classification, refinements to assess more aggressive large B-cell lymphomas and Burkitt-like lymphomas, as well as refinements to biomarkers in classical Hodgkin lymphomas.In the 2008 WHO classification, we introduced a concept of MBL. This was set at 5000 neoplastic B cells in 1 microliter of blood. This is now recognized as a precursor lesion of chronic lymphocytic leukemia (CLL). But also, the number of neoplastic cells presented in the blood may determine the prognosis. It is now thought that low count—less than 500 cells—is associated with a low rate of progression and those patients may be left alone and not followed up.

Whereas, a patient who has MBL of more than 500 cells should be followed up for risk of progression of CLL. That appears to be 1% to 2% per year per patient.

In MCL, the new WHO classification introduces the indolent variant. This indolent variant is characterized by a different biological development and is thought to arise from cells that have gone through germinal center reaction, and there are a number of biomarkers to identify the indolent variant other than the clinical parameters. These include presence of immunoglobulin gene rearrangements, as well as lack of expiration of a transcription factor called SOX-11. That is typically expressed by classical MCL. Identification of such indolent cases are important, as we heard at ASH this year that observation may be an important management strategy in MCL. Therefore, those biomarkers may select the patients most suitable for the watch-and-wait strategy.

In DLBCL, the new WHO classification introduces routine testing for activated B-cell and germinal center phenotypes. These 2 phenotypes have different clinical outcomes and may respond differently to different therapies, so this will be part of routine work up.

Currently, the best way to do this is by immunohistochemistry (IHC), and there is an algorithm we use called Hans algorithm. At ASH, we heard of other more sophisticated, molecular techniques that may eventually replace IHC techniques for assignment of cell of origin.

The other important finding at ASH was the significance of MEK, translocation, and the outcome of DLBCL. A study from The University of Texas MD Anderson Cancer Center elegantly showed that not only presence of translocation, but also extra copies of MEK, were associated with adverse outcomes. Those patients appear to benefit from more aggressive therapies—more aggressive than R-CHOP. Therefore, testing for MEK not only for translocations, but also for extra copies, may be an important strategy for patients suffering from DLBCL.

A study led by Dr. Sandeep S. Dave from Duke Cancer Institute showed that comprehensive genomic analyses might enhance risk stratification in DLBCL by adding ABC/GCB phenotypes to the mutational lenses. They were identified as high-risk and low-risk patients in this context.

How will this updated classification impact clinical practice?

Since the field of hematologic malignancies has had so much progress, will it simply be a matter of time before WHO classifications get updated again?

Are immunoglobulin genes a reliable prognostic factor?

What should community oncologists take away from these refinements?

The other important area is classical Hodgkin lymphoma, especially with the new checkpoint blockade-based therapies and their success. There were a couple of studies looking at biomarkers that could predict response to checkpoint inhibitors success. A study that used fluorescence in situ hybridization (FISH) and IHC for the PD-L1 expression in classical Hodgkin lymphoma showed that PD-L1 amplification or overexpression by IHC in the neoplastic cells was associated with response to checkpoint blockade.They integrate the new science into diagnosis; therefore, the clinicians are able to risk stratify the patients according to therapies, which forms the base of all of the clinical trials. You want a standardized diagnostic approach; otherwise, you don’t know what you’re putting into the clinical trials.The classification is dynamic. One side is driven by the biology so, if you learn more biology, you’ll understand things that you didn’t understand before. But, on the other side with therapy, it determines that a certain subset we didn’t think to classify separately may respond to a given therapy. Then, we go ahead and classify that separately. Biology-wise, we have a lot of information now. With the clinical trials, we will refine the classification more based on therapy results rather than biological studies, but it will be an integration of those 2.It is a good way of identifying low-risk and high-risk patients in CLL, and it’s now emerging in MCL. It tells you the differentiation stage of a given cell. Generally, the cells that have gone through antigen selection tend to have a better prognosis than those that are arising from more precursor cells, which do not have those mutations.More extensive testing for MEK gene rearrangements by using FISH probes is going to be 1 of the important findings. For MCL, it is trying to identify the indolent variant that may not require therapy using the biomarkers that I mentioned. For Hodgkin lymphoma, although it’s still in the early days, it may be necessary to do more biomarker studies to select patients for checkpoint blockade.

Reference

1. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-2390.