AML remains a devastating disease. Tumors with “good-risk” karyotypic abnormalities (t[8;21], inv[16]) are associated with a 50% chance of long-term disease-free survival, but the overall survival in all patients is only 15% to 30% with conventional chemotherapy. AML associated with TP53 mutations has emerged as a subtype with a particularly poor prognosis. A bright spot is the improvement in outcomes in acute promyelocytic leukemia brought about by targeted treatment with ATRA and arsenic salts. IDH inhibitors also have produced encouraging results, apparently (like ATRA) by inducing the differentiation of AML blasts. An increasing number of patients with AML are being treated with more aggressive approaches, such as allogeneic hematopoietic stem cell transplantation, which can be curative in some patients.
Fig. 12.27 Acutepromyelocyticleukemia—bonemarrowaspirate.Theneo-plasticpromyelocyteshaveabnormallycoarseandnumerousazurophilicgranules.OthercharacteristicfindingsincludeacellinthecenterofthefieldwithmultipleneedlelikeAuerrods.(Courtesy of Dr.Robert W.McKenna,Depart-ment of Pathology, University of Texas Southwestern Medical School, Dallas,Texas.)
The term myelodysplastic syndrome (MDS) refers to a group of clonal stem cell disorders characterized by
Table 12.11 WHO Classification of AML
AMLwitht(15;17)(q22;q21.1);PML/RARA fusiongeneFavorable
II. AML With Multilineage Dysplasia
III. AML,Therapy-Related
IV. AML, Not Otherwise Classified
SubclassesdefinedbyextentandtypeofIntermediatedifferentiation(e.g.,myelocytic,monocytic)
AML, Acutemyeloidleukemia;MDS, myelodysplasticsyndrome;NPM1, nucleophosmin1;WHO, WorldHealthOrganization.
http://ebooksmedicine.net maturation defects that are associated with ineffective hematopoiesis and a high risk of transformation to AML.
In MDSs, the bone marrow is partly or wholly replaced by the clonal progeny of a transformed multipotent stem cell that retains the capacity to differentiate into red cells, granulocytes, and platelets, but in a manner that is both ineffective and disordered. As a result, the marrow usually is hypercellular or normocellular, but the peripheral blood shows one or more cytopenias. The abnormal stem cell clone in the bone marrow is genetically unstable and prone to the acquisition of additional mutations and the eventual transformation to AML. Most cases are idiopathic, but some develop after chemotherapy with alkylating agents or exposure to ionizing radiation therapy.
Important new insights have come from deep sequencing of MDS genomes, which has identified a number of recurrently mutated genes. These genes can be lumped into three major functional categories, as follows:
Epigenetic factors. Frequent mutations are seen involving many of the same epigenetic factors that are mutated in AML, including factors that regulate DNA methylation and histone modifications; thus, like AML, dysregulation of the epigenome appears to be important in the genesis of MDS.
RNA splicing factors. A subset of tumors has mutations involving the RNA splicing machinery that are proposed to drive transformation by altering RNA processing, They are commonly associated with ring sideroblasts, a classic form of dysplasia that is seen in a subset of MDS.
Transcription factors. These mutations affect transcription factors that are required for normal myelopoiesis and may contribute to the deranged differentiation that characterizes MDS.