Elsevier

Seminars in Oncology

Volume 31, Issue 2, April 2004, Pages 185-197
Seminars in Oncology

The relationship of patient age to the pathobiology of the clonal myeloid diseases1

https://doi.org/10.1053/j.seminoncol.2003.12.029Get rights and content

Abstract

The incidence of the major clonal myeloid diseases, clonal cytopenias, acute, subacute (oligoblastic), and chronic myelogenous leukemia, polycythemia vera, thrombocythemia, and idiopathic myelofibrosis increases in a log-linear manner from young adulthood through advanced age. In older patients, diseases requiring cytotoxic treatment are more difficult and less successful to manage because comorbid conditions and poor performance status are more prevalent, decreasing the tolerance to therapy and increasing the frequency of side effects. This age effect is highlighted by the dramatically less favorable outcome in older than younger patients with acute myeloid leukemia with similar “favorable” cytogenetic changes. In addition, in acute and subacute myeloid leukemia in older patients, the disease is intrinsically more resistant to therapy. Overexpression of drug resistance genes and unfavorable genetic mutations are more prevalent in older patients and provide evidence that acute myeloid leukemia is often qualitatively different in these patients. The gradient of age effects is continuous; the frequency of poor outcome increasing by decade (or less). The decline in survival becomes especially steep as quinquagenarians (50-year-olds) age to nonagenarians (90-year-olds). Although improved drug schedules have led to significant improvements in event-free survival in younger patients, these improvements have been far less evident in older patients. New approaches, especially the development of drugs aimed at new targets, will be required to obtain a high frequency of long-term remissions in older patients. Agents that reverse inherent cellular drug resistance, farnesyltransferase inhibitors, BCL-2 inhibitors, and FLT3 inhibitors are early examples of such approaches.

Section snippets

The major clonal myeloid diseases

THE DESIGNATIONS for the disorders that can be encompassed by the term “myeloid leukemia” are heterogeneous. This term has been used for certain specific diagnoses, requiring the presence of leukemic blast cells in the marrow, such as acute (AML) and chronic myeloid leukemia (CML). A disorder characterized by a lower proportion of blasts in blood and marrow than in advanced AML has been referred to in the past as oligoblastic myelogenous leukemia, but now as refractory anemia with excess blasts

Aging and the clonal myeloid diseases

The relationship of patient age to the risk of developing one of the myeloid leukemias has been appreciated for most of the 20th century. The increasing risk of AML and CML with aging has become codified in the vital statistics of the industrialized countries of the world. Numerous, although less encompassing studies, have found a similar association with certain other myeloid neoplasms, including idiopathic myelofibrosis. The incidence of the less rapidly progressive hematopoietic stem cell

Cytogenetics

The therapeutic and prognostic utility of cytogenetic analysis in AML has been studied repeatedly, and a consensus has evolved on changes that predict treatment outcomes that are more or less favorable. Most studies relegate cytogenetic changes into favorable, intermediate, and unfavorable groups based on empirical studies of the response of the patient with AML to current therapeutic regimens.

Favorable cytogenetic alterations include certain balanced translocations, especially t(8;21),

Treatment approaches in older patients with acute myeloid leulemia

The treatment of older patients with AML requires individualization because the decision about the intensity of treatment is a critical function of comorbid conditions, including heart, lung, liver, kidney, neurologic, metabolic diseases, and performance status. Very advanced age may make intensive cytotoxic therapy inadvisable.42, 43 For pragmatic reasons, older patients have been defined as over 55, over 60, or over 65 years of age in different studies. No breakpoint is right or wrong. The

Results of treatment of acute myeloid leukemia in older patients

Although there has been improvement in the frequency and duration of remission and overall survival in younger patients treated for AML over the last 15 years, the improvement in treatment of older patients has been proportionately less.52

In large trials using a standard or comparable therapy of AML, about 40% of older patients (>60 years of age) enter remission. Most patients do so after one cycle of therapy, and a small proportion do so after two cycles of therapy. Of the 60% who do not enter

Newer approaches in older patients with acute myeloid leukemia

At least five approaches to increase the response rates of older patients with AML who have resistant phenotypes are in use or under study.

  • 1.

    Targeting antigens on the leukemic cell surface that are not shared by nonhematopoietic cells can increase specificity of treatment and decrease nonhematopoietic toxicity in older subjects. Gemtuzumab ozogamicin is such an agent. This monoclonal antibody targets CD33, an antigen commonly expressed on AML cells, and is conjugated to a potent cell toxin,

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    The literature review for this report was through December 2002.

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