Elsevier

Seminars in Oncology

Volume 35, Issue 4, August 2008, Pages 418-429
Seminars in Oncology

Acute myeloid leukemia
Therapy-Related Myeloid Leukemia

https://doi.org/10.1053/j.seminoncol.2008.04.012Get rights and content

Therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/t-AML) are thought to be the direct consequence of mutational events induced by chemotherapy, radiation therapy, immunosuppressive therapy, or a combination of these modalities, given for a pre-existing condition. The outcomes for these patients have been poor historically compared to people who develop de novo AML. The spectrum of cytogenetic abnormalities in t-AML is similar to de novo AML, but the frequency of unfavorable cytogenetics, such as a complex karyotype or deletion or loss of chromosomes 5 and/or 7, is considerably higher in t-AML. Survival varies according to cytogenetic risk group in t-AML patients, with better outcomes being observed in those with favorable-risk karyotypes. Treatment recommendations should be based on performance status and karyotype. A deeper understanding of the factors that predispose patients to the development of therapy-related myeloid leukemia would help clinicians monitor patients more carefully after treatment for a primary condition. Ultimately, this knowledge could influence initial treatment strategies with the goal of decreasing the incidence of this serious complication.

Section snippets

Subtypes of Therapy-Related Myeloid Leukemia

The characteristics of therapy-related leukemia and the timing of its development after a primary diagnosis depend on the exposure to specific agents, as well as the cumulative dose and dose intensity of the preceding cytotoxic therapy.

In the classic form of therapy-related leukemia that follows treatment with alkylating agents and/or radiation therapy, the blood and bone marrow findings resemble those seen in primary MDS, although the degree of dysgranulopoiesis and dysmegakaryocytopoiesis is

Risk Factors for the Development of Therapy-Related Leukemias

The etiology and specific factors that predispose to the development of therapy-related leukemia have been difficult to study. It has not yet been possible to determine whether the development of t-MDS/t-AML is a stochastic event, occurring by chance, or whether certain individuals are at higher risk. However, more recent studies have employed newer technology that allows the rapid sequencing of a large number of single nucleotide polymorphisms (SNPs) and suggest that at least a fraction of

Genetic Pathways and Cooperating Mutations in the Etiology of Therapy-Related Myeloid Leukemia

Particular mechanisms of DNA damage that lead either to chromosomal deletions or balanced translocations may underlie the differences in latencies between the two main forms of therapy-related leukemia.1, 27 In the case of chromosomal deletions, one allele of a putative tumor-suppressor gene may be inactivated. However, before the affected cell would gain a proliferative advantage, the second allele might have to be deleted or mutated also. In some cases, the first allele may be inactivated in

Therapy-Related Leukemia after Breast Cancer

Although long-term survivors of Hodgkin's disease were among the first patients to suffer the development of t-AML, this complication is now increasingly observed in those patients treated for solid tumors. Several large studies have examined the risks for women receiving adjuvant chemoradiotherapy for breast cancer. Several groups have addressed the question as to whether the addition of G-CSF to routine therapy regimens contributes to the risk of developing t-AML out of the concern that G-CSF

Therapy-Related Leukemia after Autologous Hematopoietic Cell Transplantation

Several thousand autotransplants are performed each year for patients with relapsed lymphoma and other diseases. Estimates of the incidence of therapy-related leukemia among these lymphoma and Hodgkin's disease patients range between 1% and 14% at 3 to 15 years.38 The risk appears lower in patients undergoing autologous hematopoietic cell transplantation (HCT) for breast or germ cell cancers or for myeloma. Important risk factors include age, extent of prior therapy, and exposure to certain

Factors That Influence Outcome in t-AML

Therapy-related myeloid leukemia is generally a fatal disease. The life-threatening complications of this disorder are the result of persistent and profound cytopenias due to the failure of normal hematopoiesis regardless of the fraction of myeloblasts accumulating in the bone marrow or blood. There has been general agreement that patients with t-AML have shorter survivals than patients with de novo AML. Supportive care is still considered by many to be the standard management.

A number of

Treatment of Therapy-Related Myeloid Leukemia

The survival of patients with therapy-related leukemia is often poor despite prompt diagnosis and treatment. However, there is a paucity of prospective treatment data since these patients are most often excluded from frontline clinical trials. There are no randomized studies comparing standard AML therapy to other forms of treatment. In a nationwide Japanese study of 256 patients with t-MDS (41%) or t-AML (59%), a poor prognosis was associated with abnormalities of chromosome 5,

HCT for t-AML

The treatment most likely to cure t-AML is allogeneic HCT. Several small case series have described the outcomes of these patients, and the survival rate appears to be about 20% to 30%.1, 42 However, chronic and cumulative toxicities from prior chemoradiotherapy have an impact on the ability to perform HCT and adversely affect survival. Early deaths from regimen-related toxicity are more common after HCT for therapy-related leukemia than for primary AML.

In an analysis of 70 patients (31 with

Treatment of t-AML With Balanced Chromosomal Rearrangements

In marked contrast to the poor outcome overall for t-AML, those patients who develop t-APL with t(15;17) or those with t(8;21) or inv(16) have response rates that are similar to patients with de novo AML with the same chromosomal rearrangements, although overall survival is less. In a report on 106 cases of t-APL identified between 1982 and 2001 in France, Spain, and Belgium, the characteristics of the t-APL patients were similar to those of de novo APL patients.46 In addition, more than 80% of

The Importance of Cytogenetic Abnormalities in Predicting Patient Outcomes

The most informative data on the prognostic impact of karyotype on outcome in t-AML were reported by the German AML Cooperative Group (AMLCG).49 This group compared karyotype analysis and survival between 93 patients with t-AML and 1,091 patients with de novo AML, all of whom received intensive treatment. Favorable, intermediate, and unfavorable karyotypes, respectively, were observed in 26%, 28%, and 46% of t-AML patients, and in 22%, 57%, and 20% of de novo AML patients. Overall, the median

Recommendations for Treatment of t-AML

Figure 3 shows a treatment algorithm for the management of patients who develop therapy-related myeloid leukemia. Primary considerations are the patient's performance status, which reflects age, comorbidities, the status of the primary disease, and the presence of complications from primary therapy, as well as the clonal abnormalities detected in the t-AML cells. In general, t-AML patients should be encouraged to participate in prospective clinical trials that are appropriately designed for

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    Supported in part by Grants No. CA40046 and CA14599 from the National Cancer Institute.

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