Classification of AML

With the advent of routine cytogenetic characterization of AML, coupled with improved understanding of the molecular basis of the disease achieved through cloning of chromosomal breakpoint regions and identification of mutations in a wide range of genes, it has become clear that many primary AML-associated lesions that define biological entities are heterogeneous when classified according to FAB type.7 This underlies the finding that the diagnostic karyotype is more highly predictive of initial response to therapy and risk of relapse than is the FAB type, which reflects to a limited degree the molecular and clinical diversity of the disease. In the latter respect it has become apparent that cases of AML arising following previous chemotherapy or radiotherapy or on the background of a prior hematologic disorder such as myelodysplasia (MDS) are associated with a generally poorer prognosis than cases arising de novo. Moreover, there is increasing evidence, for example, karyotypic similarities and high rates of P-glycoprotein (PGP) overexpression, to suggest that a significant proportion of AML cases arising in older patients are biologically akin to secondary leukemias. These additional facets, that is, genetic and clinical features that do not form a part of the FAB classification but are highly pertinent to determining treatment approach for patients with AML and predicting the likelihood of cure, have been partly taken into account in the recent World Health Organization (WHO) classification (reviewed in Reference 15; see Table 30-4). The WHO system still, however, retains a morphological classification for all cases that do not fall into its "specific" clinical, morphological, or cytogenetic groups. These morphological groups are based on the FAB categories M0, M1, M2 M4, M5, M6, and M7, with the addition of three new categories, namely, acute basophilic leukemia, acute panmyelosis with marrow fibrosis, and myeloid sarcoma. A major difference between the FAB and WHO classifications lies in the minimum bone

Table 30-4. Classification of AML According to the World Health Organization

AML with Recurrent Genetic Abnormalities t(8;21)/AML1-ETO

AML with abnormal eosinophils and mv(16){p13q22)/t(16\16)(p13\q22)/CBFB-MYH11 APL with t(15;17Xq22;q12~21)/PML-RARA and variants AML with 11q23/MLL abnormalities

AML with Multilineage Dysplasia

Following MDS or myeloproliferative disorder (MPD) No previous history of MDS or MPD, but with dysplasia in >50% of cells in two or more myeloid lineages

AML and Myelodysplastic Syndromes, Therapy Related

Alkylating agent/radiation-related Topoisomerase II inhibitor-related Others

AML, Not Otherwise Categorized, Classified As

AML, minimally differentiated

AML without maturation

AML with maturation

Acute myelomonocytic leukemia

Acute monoblastic/acute monocytic leukemia

Acute erythroid leukemia (erythroid/myeloid and pure erythroleukemia) Acute megakaryoblastic Acute basophilic

Acute panmyelosis with myelofibrosis Myeloid sarcoma

Table 30-5. Prognostic Factors for Subsequent Relapse in Patients

with Newly Diagnosed AML

Pretreatment Predictors

Major Other

Karyotype

Elevated WBC

Molecular

Elevated LDH

FLT3 ITD

Secondary disease*

NPM1 mutation

Dysplastic features*

Older Age

BCL2/BAX ratio

Resistance protein expression e.g. PGP*

TP53 mutation*

Autonomous growth of AML blasts in

culture*

Immunophenotype e.g. CD34

expression*

Expression of chemotherapy

metabolizing enzymes

Expression of BAALC, EVI1, and ERG

Posttreatment Predictors

Initial response (post-induction blast count)

MRD assessment

Many factors (indicated by *) previously considered to confer

adverse risk have been shown to be closely related to cytogenetic

risk group.

WBC, presenting white blood cell count; LDH, lactate dehydro-

genase; PGP, P-glycoprotein; MRD, minimal residual disease.

marrow blast percentage as a cutoff separating MDS from AML, with the WHO system dropping the FAB threshold of 30% blasts down to 20%. Moreover, cases with clonal abnormalities in the form of t(15;17)(q22;q12~21),inv(16), or t(8;21) are deemed to have AML irrespective of blast percentage, according to the WHO system.

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