The first edition of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults, published in 2010, has found broad acceptance by physicians and investigators caring for patients with AML. Recent advances, for example, in the discovery of the genomic landscape of the disease, in the development of assays for genetic testing and for detecting minimal residual disease (MRD), as well as in the development of novel antileukemic agents, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. The recommendations include a revised version of the ELN genetic categories, a proposal for a response category based on MRD status, and criteria for progressive disease

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An International Working Group met to revise the diagnostic and response criteria for acute myelogenous leukemia originally published in 1990, as well as to provide definitions of outcomes and reporting standards to improve interpretability of data and comparisons among trials. Since the original publication, there have been major advances in our understanding of the biology and molecular genetics of acute leukemia that are clinically relevant and warrant incorporation into response definitions. Differences from the 1990 recommendations included a category of leukemia-free state, new criteria for complete remission, including cytogenetic and molecular remissions and remission duration. Storage of viable blasts for correlative studies is important for future progress in the therapy of these disorders.

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The introduction of all-trans retinoic acid (ATRA) and, more recently, arsenic trioxide (ATO) into the therapy of acute promyelocytic leukemia (APL) has revolutionized the management and outcome of this disease. Several treatment strategies using these agents, usually in combination with chemotherapy, but also without or with minimal use of cytotoxic agents, have provided excellent therapeutic results. Cure of APL patients, however, is also dependent on peculiar aspects related to the management and supportive measures that are crucial to counteract life-threatening complications associated with the disease biology and molecularly targeted treatment. The European LeukemiaNet recently appointed an international panel of experts to develop evidence-and expert opinion-based guidelines on the diagnosis and management of APL. Together with providing current indications on genetic diagnosis, modern risk-adapted front-line therapy and salvage treatment, the review contains specific recommendations for the identification and management of most important complications such as the bleeding disorder, APL differentiation syndrome, QT prolongation and other ATRAand ATO-related toxicities, as well as for molecular assessment of response to treatment. Finally, the approach to special situations is also discussed, including management of APL in children, elderly patients, and pregnant women.

Administration of the antibody-targeted chemotherapy agent Mylotarg to patients with CD33-positive AML in first relapse induces complete remissions with what appears to be a favorable safety profile.

BACKGROUNDElderly patients (age ≥ 65 years) with acute myeloid leukemia (AML) generally have a poor prognosis. AML‐type therapy results are often derived from studies in younger patients and may not apply to elderly AML. Many investigators and oncologists advocate, at times, only supportive care or frontline single agents, Phase I–II studies, low‐intensity regimens, or ‘targeted’ therapies. However, baseline expectations for outcomes of elderly AML with ‘standard’ AML‐type therapy are not well defined. The aim was to develop prognostic models for complete response (CR), induction (8‐week) mortality, and survival rates in elderly AML, which would be used to advise oncologists and patients of expectations with standard AML type therapy, and to establish baseline therapy results against which novel strategies would be evaluated.METHODSA total of 998 patients age ≥ 65 years with AML or high‐risk myelodysplastic syndrome (> 10% blasts) treated with intensive chemotherapy between 1980 and 2004 were analyzed. Univariate and multivariate analyses of prognostic factors associated with CR, induction (8‐week) mortality, and survival used standard methods.RESULTSThe overall CR rate was 45% and induction mortality 29%. Multivariate analysis of prognostic factors identified consistent independent poor prognostic factors for CR, 8‐week mortality, and survival. These included age ≥ 75 years, unfavorable karyotypes (often complex), poor performance (3–4 ECOG [Eastern Cooperative Oncology Group]), longer duration of antecedent hematologic disorder, treatment outside the laminar airflow room, and abnormal organ functions. Patients could be divided into: 1) a favorable group (about 20% of patients) with expected CR rates above 60%, induction mortality rates of 10%, and 1‐year survival rates above 50%; 2) an intermediate group (about 50–55% of patients) with expected CR rates of 50%, induction mortality rates of 30%, and 1‐year survival rates of 30%; and 3) an unfavorable risk group (about 25–30% of patients) with expected CR rates of less than 20%, induction mortality rates above 50%, and 1‐year survival rates of less than 10%.CONCLUSIONSPrognostic models, based on standard readily available baseline characteristics, were developed for elderly patients with AML, which may assist in therapeutic and investigational decisions. These predictive models, based on a retrospective analysis, will require validation in independent study groups. Cancer 2006. © 2006 American Cancer Society.

IntroductionNormal and leukemic hematopoietic cells and stem cells reside in the bone marrow in specialized areas ("niches") that provide the structural and physiologic conditions for their growth and survival. 1 Subpopulations of leukemic cells can be sequestered in niches and thereby evade chemotherapy-induced death. 2 We and others have reported that stromal cells protect acute myeloid leukemia (AML) and chronic lymphocytic leukemia cells from the apoptosis induced by chemotherapy. [3][4][5][6] While the mechanisms of stroma-mediated protection are pleiotropic and involve a complex interplay of stroma-produced cytokines, chemokines, and adhesion molecules, the stroma-secreted chemokine stromal-derived factor 1␣ (SDF-1␣) and its cognate receptor CXCR4 have recently emerged as critical mediators of stromal/leukemic cell interactions. 7,8 SDF-1␣ and CXCR4 primarily regulate the migration, homing, and mobilization of hematopoietic cells. 9,10 Binding of SDF-1␣ to CXCR4 causes CXCR4 to be incorporated into lipid rafts 11 and increases its phosphorylation. 12 The latter leads to prolonged activation of the extracellular signaling-regulated kinase (ERK) and phosphoinositol 3-kinase (PI3K) pathways, 13 which are key signaling pathways that promote leukemia cells survival. 14,15 Both surface and intracellular 16 CXCR4 levels were found to be elevated in a subset of AML cases. Further, CXCR4 has been shown to mediate the homing and engraftment of AML cells to the bone marrow of nonobese diabetes (NOD)/severe combined immunodeficiency (SCID) mice. 17,18 Finally, CXCR4 was recently reported to be expressed at higher levels in cases of AML associated with an internal tandem duplication (ITD) type of mutation of the gene that encodes fetal liver tyrosine . 19 This is one of the most frequent mutations in AML, which confers poor response to chemotherapy and only transient response to FLT3 inhibitors. 20,21 Our recent studies, in addition, indicated that CXCR4 expression is associated with poor prognosis in patients with diploid AML regardless of FLT3 mutation status. 22,23 Altogether, these findings suggest that disruption of these interactions by SDF-1␣/CXCR4 antagonists represents a novel strategy for targeting leukemia/bone marrow microenvironment interactions. We have reported that inhibition of CXCR4 by specific synthetic peptides (ie, RCP168) interferes with stromal/ leukemic cell interactions and increases the sensitivity of leukemic cells to chemotherapy. 24 In this study, we used AMD3465 (Anormed and Genzyme, Cambridge, MA), a second-generation smallmolecule reversible inhibitor of SDF-1␣/CXCR4 with a half maximal inhibitory concentration (IC 50 An Inside Blood analysis of this article appears at the front of this issue.The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use on...