New paths through hematologic neoplasms

Karen Titus

March 2023—Updated classifications for hematologic neoplasms are here. Let the complications continue.

As with other specialties, hematopathology has been absorbing advances gleaned from molecular and genetic data. In some cases, this can tilt diagnosis away from primarily immunophenotypic approaches. It might lead to splits in what was formerly a single entity. On occasion, it might suggest further testing options that could be of value to patients now, or possibly at a date down the road.

Or it might just leave pathologists and their clinical colleagues peering at a lack of data, knowing they have to make decisions nonetheless.

Two groups—the World Health Organization and the International Consensus Classification—have put forth classifications to help physicians sort through the complexities.

The WHO published a beta version of the fifth edition of its Classification of Haematolymphoid Tumours in July 2022 (https://tumourclassification.iarc.who.int). Joseph Khoury, MD, the Stokes-Shackleford professor and chair of the Department of Pathology and Microbiology, University of Nebraska Medical Center, and chair of the CAP Cancer Committee, says he expects the final version of the WHO classification to be available this summer, when it will be published as another volume of the well-known Blue Books. In the meantime, the following papers delved into the intricacies of the classification:

• Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022;36[7]:1703–1719.
• Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: lymphoid neoplasms. Leukemia. 2022;36[7]:1720–1748.

The ICC published its classification of myeloid neoplasms, acute leukemias, and mature lymphoid neoplasms in September 2022 (https://bit.ly/ICC_09152022) in the following two papers:

• Arber DA, Orazi A, Hasserjian RP, et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022:140[11]:1200–1228.
• Campo E, Jaffe ES, Cook JR, et al. The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the clinical advisory committee. Blood. 2022;140[11]:1229–1253.

Classifications can sometimes feel as torturous—and perhaps as inscrutable—as a 16th-century sonnet. How best to encode complex matter into a universal format?

A new editorial governance structure was created to oversee the fifth edition of the WHO classification, namely, an editorial board that includes standing members—selected representatives from major medical and scientific organizations around the world—who oversee the entire series, in addition to expert members, selected for their expertise relevant to a particular volume. “Importantly, this allowed the selection of a multidisciplinary editorial team,” Dr. Khoury says, composed of pathologists, geneticists, oncologists, hematologists, and others, to produce the WHO Classification of Haematolymphoid Tumours. (Dr. Khoury is chair of the standing editorial board.) This governance structure abides by WHO rules of engagement (https://bit.ly/WHA69-10) and “permits a transparent process with appropriate checks and safeguards,” he says.

The ICC, says Daniel Arber, MD, the Donald West and Mary Elizabeth King professor of pathology and chair of the Department of Pathology, University of Chicago, used an approach that was similar to the one used in previous WHO editions of the classification; indeed, he notes, a number of authors on the ICC classification were involved with previous WHO classifications. Dr. Arber was the onsite organizer for the clinical advisory committee meeting and led the effort to develop the myeloid neoplasms and acute leukemias portion of the ICC classification.

Clinical input was key to developing both the WHO and the ICC classifications, say Dr. Khoury and Dr. Arber.

As the ICC developed its guideline, Dr. Arber says, the advisory committee served a key role. “The approach we took is to have pathologists come up with potential changes, based on new publications that might impact classification, and then have the clinicians comment on them.” An agreement from both pathologists and clinicians led to specific changes, he says.

“Particularly around genetics, there have been a lot of changes since the revised fourth edition of WHO,” from 2016, he says. “So the ICC incorporated those and moved more toward a molecular classification, particularly on the myeloid side.”

On the lymphoma side, Dr. Arber says, molecular aspects were also taken into consideration. He draws particular attention to follicular lymphoma types and T-cell follicular helper type lymphomas, calling them “still somewhat immunophenotypic driven but still informed by molecular studies.”

Dr. Arber is the lead author on the aforementioned Blood article that covers the myeloid and acute leukemia sections of the ICC classification.

The number of genetic categories has been expanded for the acute leukemias, he says, and the approach to acute myeloid leukemia with myelodysplasia-related changes adopts a more molecular approach.

In AML, he says, the list of cytogenetic abnormalities and gene mutations continues to grow, which has continued to be reflected in the classifications over the years. In some cases, it’s becoming more clear which mutations are drivers of disease.

“For acute lymphoblastic leukemia lymphoma,” he continues, “there are a lot of new genetic categories that have been discovered. People aren’t testing for them yet, but they are biologically relevant. So they are included in the classification with the hope that labs will start doing more testing for them.”

This is familiar territory for classifications, Dr. Arber says. Even if tests aren’t clinically available for mutations, drawing attention to them in classifications “helps drive labs to do this testing” when it becomes available, given their potential importance.

This approach does pay off, he adds. “It has helped lead to more targeted therapies for these patients.” And even when highly specialized testing is limited to only a few institutions—he cites testing for acute lymphocytic leukemia that is done at St. Jude Children’s Research Hospital as an example—“they identify subtypes that can be tested by other methods, such as FISH, which labs can adopt.”

More data has emerged in the area of chronic myelomonocytic leukemia, Dr. Arber says. The revised fourth edition of the WHO classification, he says, contains a category called CML-0 “defined by really low blast counts”—less than two percent blasts in blood and less than five percent blasts in bone marrow. Now, with more data available on this type of CMML, it appears that this classification isn’t as prognostically useful or as reproducible as was once thought, so the ICC classification eliminates this category.

Acute myeloid leukemias with mutated CEPBA is another area of change in the ICC classification. In the fourth edition of WHO, Dr. Arber says, any CEPBA mutation was seen as a good prognostic indicator. With additional data, he says, “Now it’s clear that the only thing that impacts prognosis is having an in-frame mutation in the bZIP region.”

The WHO classification, as noted, is in the beta version. “The value of the beta version is to provide a public input period while allowing the scientific and medical community to begin familiarizing itself with the new classification,” Dr. Khoury says. “This allows experts to provide feedback and any edits, comments, or corrections they might have.”

Nonetheless, the beta version is unlikely to change substantially, according to Dr. Khoury, who is the lead author on the aforementioned Leukemia article that details the section on myeloid and histiocytic/dendritic neoplasms. “The classification itself will not change,” he says. This edition marks the first time that the initial framework of the hematolymphoid classification was made available for public input early in the process, Dr. Khoury says. “It is a statement of inclusion, openness, and transparency. The availability of the beta version falls in the same line.” The fifth edition in its beta version is already being discussed at national and international meetings, he adds.

The classification builds on the work of prior classifications. One significant change overall is that it integrates advances in the molecular genetic characteristics used to classify cancers currently, Dr. Khoury says. “In addition, the fifth edition of the WHO hematolymphoid classification is now, for the first time, integrated into a broader hierarchical structure and a relational database that unifies the classification for all types of cancers recognized by the WHO.”