Response: Factors considered in the 2008 WHO classification of myeloid neoplasms and acute leukemias

We appreciate the positive comments of Drs Wandt, Haferlach, Thiede, and Ehninger regarding the 2008 World Health Organization (WHO) classification of acute leukemias and their concern regarding the clinical significance of the subgroup of acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) defined only by morphologic dysplasia. The members of the WHO myeloid writing committee and of the Myeloid Clinical Advisory Committee (MCAC) were aware of the publications of these authors^1,2  that suggested that in multivariate analyses, myelodysplasia-related morphologic abnormalities had no independent prognostic significance compared with myelodysplasia-related cytogenetic abnormalities. Indeed, their data supported the addition of the subgroup of AML-MRC defined by specific myelodysplasia-related cytogenetic abnormalities in the revised 2008 WHO classification,³  and it also prompted discussion at the MCAC meeting as to whether AML-MRC defined by morphologic criteria alone should remain in the classification. However, data presented at that meeting and some published subsequently⁴  suggested such a subgroup may yet prove to have clinical relevance.

Many patients who meet only the WHO morphologic criteria for AML-MRC would be otherwise classified as “AML, not otherwise specified (NOS).” Intuitively, severe dysplasia in the majority of maturing leukemia cells seems to be as much of a unifying factor for classification and further investigation as dispersing such cases among the categories of AML, NOS that also lack clear prognostic significance. Weinberg and colleagues⁴  used the 2008 WHO criteria to compare patients with AML-MRC (most defined solely by morphologic multilineage dysplasia) with patients classified as AML, NOS, and found patients with AML-MRC were significantly older and had decreased frequency of mutated CEBPA and significantly worse overall and progression-free survival than patients with AML, NOS. This prognostic difference remained when cases classified as AML-MRC solely on the basis of multilineage dysplasia were compared, which supports the notion that subclassification by morphology as AML-MRC is clinically more relevant than classification as AML, NOS. We can only speculate as to why multilineage dysplasia had clinical significance in the study by Weinberg et al, but not in the larger studies cited.^1,2  Of note is that neither of the latter studies used the WHO classification criteria. The study by Haferlach et al included only AML patients with 30% or more blasts, which would exclude a significant number of cases of AML-MRC were the WHO criterion for AML of 20% or more blasts applied. Wandt et al included cases of therapy-related AML, which is recognized as a separate category in the WHO classification. Furthermore, both studies used only blood and bone marrow aspirate smears whereas Weinberg et al also evaluated bone marrow biopsies. Megakaryocytic dysplasia may be difficult to identify on aspirated material alone but is usually readily observed in core biopsies. Also some cases with AML-MRC present with fibrosis, which may limit evaluation of aspirate material.

A second issue raised by some members of the MCAC in favor of retaining the morphologic diagnosis of AML-MRC was that some such cases might be patients evolving to AML from a previously unrecognized myelodysplastic syndrome who have a borderline blast count of barely 20% or more, and who might be better served initially by judging the pace of their disease rather than immediately categorizing them as AML, NOS.

The WHO writing committees were also aware of the data regarding the incidence and clinical significance of FLT3 and NPM1 mutations in the setting of AML with multilineage dysplasia.²  However, what was not clearly defined is the impact of these mutations in patients who have AML-MRC. More data are needed to decide whether a patient defined morphologically to have AML-MRC with mutated NPM1 would be best categorized as AML-MRC, as AML, NOS, or in the provisional category of AML with mutated NPM1.

Therefore, in view of data that morphology may identify a clinically relevant group of patients with AML-MRC as well as a group of patients in evolution from myelodysplastic syndrome to AML for whom treatment options might vary, and the uncertainty as to classification when multilineage dysplasia and specific genetic mutations coexist, the consensus of the MCAC was to retain the morphologically defined AML-MRC category in the revised WHO classification and collect additional information regarding its clinical significance. However, a key principal of the WHO classification is that it is amenable to change. Forums such as this and the MCAC meetings are important to form a consensus opinion through which changes in the classification can occur. Perhaps in the next edition of the WHO Classification there will be a different consensus opinion regarding AML-MRC and multilineage dysplasia based on additional data.