Advances in the identification of unique biomarkers associated with some myeloid neoplasms and acute leukemias – thanks in part to gene-expression analyses and next-generation sequencing – have prompted the World Health Organization (WHO) to update its 2008 publication on the classification of tumors of the hematopoietic and lymphoid tissues.1
The revised monograph was recently published in Blood, along with a revision of the WHO’s 2008 classification of lymphoid neoplasms.
“This 2016 classification is not a major overhaul of the disease categories. Rather, it is intended to incorporate new knowledge of these disorders obtained since the 2008 publication and is a revision of that classification,” the authors, led by Daniel A. Arber, MD, from Stanford University in Stanford, California, explained.
“With respect to myeloid neoplasms, Dr. Arber and colleagues emphasize that many novel molecular findings with diagnostic and/or prognostic importance have been incorporated into the 2016 revision,” Mario Cazzola, MD, an associate editor of Blood, wrote in an editorial accompanying the updated classification.2 “[This revision] represents the efforts of pathologists working closely with clinicians and geneticists. In the next few years, we should continue this collaboration to further improve the integration of clinical features, morphology, and genetics.”
The revised recommendation is necessary due to the discoveries in diagnostic and prognostic markers; improved characterization and standardization of morphologic features; and the clinical-pathologic studies that call for an integrated approach incorporating hematologic, morphologic, cytogenetic, and molecular genetic findings.
To develop this new monograph, the WHO convened a clinical advisory committee in early 2014 comprising nearly 100 pathologists, hematologists, oncologists, and geneticists to propose revisions to the 2008 classification.
Read below for some of the major and proposed changes. For the full updated classification, visit bloodjournal.org.
The categories of myeloproliferative neoplasms (MPNs) have not significantly changed since the 2008 edition, the authors noted, “but discoveries of new mutations and improved understanding of the morphologic features of some entities have impacted the diagnostic criteria for the disease entities.”
Chronic myeloid leukemia (CML), BCR-ABL1–positive: Most cases of CML can be diagnosed from peripheral blood findings combined with detection of t(9;22)(q34.1;q11.2) or BCR-ABL1. Newly diagnosed patients have a much better prognosis when treated with tyrosine kinase inhibitors (TKIs), but regular monitoring for BCR-ABL1 and the potential for TKI resistance should be conducted to detect disease progression.
Mastocytosis: Discoveries of new genetic mutations associated with these diseases have changed their diagnostic criteria. Mastocytosis is no longer considered a subgroup of the MPNs due to its unique clinical and pathologic features and is now a separate disease category in the classification. Under its own classification, mastocytosis includes:
- Cutaneous mastocytosis
- Systemic mastocytosis
- Indolent systemic mastocytosis
- Smoldering systemic mastocytosis
- Systemic mastocytosis with an associated hematologic neoplasm
- Aggressive systemic mastocytosis
- Mast cell leukemia
- Mast cell sarcoma
The myelodysplastic syndromes (MDS)/MPN category was introduced in the third edition of the WHO classification to include MPNs with clinical, laboratory, and morphologic features that overlap between MDS and MPN, the authors explained.
MDS/MPN with ring sideroblasts and thrombocytosis has been converted from a provisional to a full entity.
Chronic myelomonocytic leukemia (CMML): Targeted sequencing of mutated genes can detect a high proportion of cases, with SRSF2, TET2, and ASXLI being the most commonly mutated genes. Newly diagnosed CMML requires both the presence of persistent monocytosis ≥1 x 109/L and monocytes accounting for ≥10 percent of the white blood cell differential count. CMML is now separated into two subtypes: proliferative type (white blood cell [WBC] count ≥13×109/L) and dysplastic type (WBC count <13 x 109/L) with differences related to aberrancies in the RAK/MAPK signaling pathways.
The updated guidelines have changed the terminology for adult MDS to remove “refractory anemia” and “refractory cytopenia” and replaced them with MDS with the following modifiers: single versus multi-lineage dysplasia, ring sideroblasts, excess blasts, or the del(5q) cytogenetic abnormality. No changes were made for childhood MDS.
Since the 2008 monograph, a large amount of data are available on recurring mutations in MDS. Targeting sequencing can detect mutations in 80 to 90 percent of MDS patients, the most common of which are SF3B1, TET2, SRSF2, ASXL1, DNMT3A, RUNX1, U2AF1, TP53, and EZH2. The TP53 mutation is associated with aggressive disease in MDS and appears to predict poorer response to lenalidomide treatment in patients with del(5q).
This monograph includes a section on myeloid neoplasms with germline predisposition, including the following:
- Myeloid neoplasms with germline predisposition without a preexisting disorder or organ dysfunction
- Myeloid neoplasms with germline predisposition and preexisting platelet disorders
- Myeloid neoplasm with germline predisposition and other organ dysfunction
Acute Myeloid Leukemia
A new provisional category of acute myeloid leukemia (AML) with BCR-ABL1 has been established to recognize these rare, de novo AML cases that may benefit from treatment with TKI therapy. Though the diagnostic distinction between de novo AML with BCR-ABL1 and blast transformation of CML may be difficult to distinguish, the significance of detecting this targetable fusion is important. Preliminary data suggest that deletion of antigen receptor genes (IGH, TCR), IKZF1, and CDKN2A may support a diagnosis of de novo AML with BCR-ABL1 versus BP-CML.
AML with CEBPA is classically associated with bi-allelic, but not single, mutations of the gene and has resulted in a change in the definition to require the presence of biallelic mutations. Due to the lack of prognostic significance of multilineage dysplasia in patients without MDS-associated cytogenetic findings and with a mutation of NPM1 or biallelic mutation of CEBPA, these mutations now supersede the presence of multilineage dysplasia in the classification.
In addition, a provisional category of AML with mutated RUNX1 has been added to the classification for de novo AML.
Under the classification for AML, not otherwise specified, the subcategory of acute erythroid leukemia, erythroid/myeloid type (previously defined as having ≥50% bone marrow erythroid precursors and ≥20% myeloblasts among non-erythroid cells) has been removed. Myeloblasts are always counted as a percentage of total marrow cells, with the majority of these cases having less than 20 percent total blast cells, thus classified as MDS.
Acute Leukemias of Ambiguous Lineage
Preliminary data suggest that mixed phenotype acute leukemia with t(9;22) respond favorably to TKI treatment.
New provisions have been added for B-cell lymphoblastic leukemia/lymphoma (B-ALL) and T-cell lymphoblastic leukemia/lymphoma (T-ALL). For B-ALL, two provisional entities with recurrent genetic abnormalities have been recognized:
- B-ALL with intrachromosomal amplification of chromosome 21
- Amplification of a portion of chromosome 21
- Occurs in about 2% of children with ALL, especially older children with low WBC counts
- Associated with an adverse prognosis, which, to some extent, can be overcome with more aggressive therapy
- B-ALL with translocations involving tyrosine kinases or cytokine receptors
- Associated with an adverse prognosis and responses of some cases to TKIs
- Difficult to define in the clinical setting
Though studies have investigated the genetic mechanisms of T-ALL, assays have not yet been standardized and prognostic implications are still controversial.
- Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia. Blood. 2016 April 11. [Epub ahead of print]
- Cazzola M. Introduction to a review series: the 2016 revision of the WHO classification of tumors of hematopoietic and lymphoid tissues. Blood. 2016 April 11. [Epub ahead of print]
Editor’s Note: The World Health Organization also revised its classification of lymphoid neoplasms, published in the March 15, 2016, edition of Blood. Look for our previous coverage of these revisions in “What To Call What We Treat, Part I: WHO Releases Updated Classification of Lymphoid Neoplasms” in our May issue.