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By William B. Ershler, MD
Approximately 10% of patients with newly diagnosed acute myelogenous (AML) leukemia have a history of prior treatment with chemotherapy, radiation, or both (t-AML).1,2 Detectable chromosomal changes are more common in t-AML and are probably the consequence of non-lethal mutations occurring in hematopoietic progenitor cells that render those cells susceptible to leukemic transformation.3
The latency period between the prior treatment and the appearance of AML varies and seems to depend on the type of prior treatment. For example, for those with a history of radiation or alkylating agent exposure, the period is usually 5-10 years, whereas for those with prior exposure to topoisomerase II inhibitors, latency is considerably shorter, perhaps 1-5 years.4,5 The varying latency probably relates to the pathogenesis, as those with alkylating agent/radiation exposure are more likely to have unbalanced cytogenetic abnormalities, such as loss of all or parts of chromosome 5 and/or 7, whereas those previously treated with topoisomerase II inhibitors more frequently present with balanced chromosomal rearrangements involving MLL, RUNX1, and PML-RARA.2,6-8 Nonetheless, this distinction is of marginal clinical value as currently most patients with t-AML have a history of both types of treatment.
There may be a genetic predisposition to t-AML.3,9 Furthermore, those patients with a history of prior malignancy not treated with either chemotherapy or radiation also may share some features of t-AML. In a recent review of close to 3000 patients with AML who had been enrolled in any of six trials conducted by the German-Austrian AML Study Group (AMLSG),10 77 patients had prior malignancies but had not been treated with chemotherapy or radiation. The median latency period for these patients was 5 years and there was a trend toward more adverse cytogenetic features. However, overall survival for this group was comparable to de novo AML and better than t-AML.
Most series, including this recently reported German-Austrian AMLSG, find the spectrum of cytogenetic abnormalities in t-AML to be similar to de novo AML, but find the frequency of unfavorable cytogenetics, such as complex karyotype or deletion or loss of chromosomes 5 or 7, to be strikingly higher in t-AML. For example, in the large German-Austrian series, 75% of t-AML patients had abnormal karyotypes compared to 51% of those with de novo AML.10 Notably, although there was no difference in the frequency of favorable risk abnormalities, there was a marked increase in adverse karyotypic changes, including -5, 5q-, -7, 7q-, t(9;11), t(v;11)(v;q23), abnormal (17p), complex karyotypes, and monosomal karyotypes.
Although complete response rates to aggressive chemotherapy are achievable, progression-free and overall survival are worse for t-AML than de novo AML. In a review of 644 t-AML patients treated with "standard" AML regimens, only 28% achieved a CR.11 Yet, in the German Austrian series, CR rates among those with t-AML were comparable to de novo AML, around 65%. Yet, the relapse-free survival (RFS) at 4 years for those with t-AML was 24.5% compared to 39.5% for those with de novo AML. However, these numbers are subject to selection bias because t-AML patients are typically older and, at least in the United States, are less likely to be referred for enrollment in the aggressive treatments such as those undertaken by this cooperative group.
In a recent comprehensive review on the topic, Godley and Larsen recommend that treatment be based on karyotype and performance status.12 For those with good performance status and normal or favorable karyotypic changes, standard induction therapy followed by either high-dose cytarabine or allogeneic hematopoietic cell transplant is recommended. For those with good performance status but unfavorable karyotypes, investigational therapy was recommended. For patients with poor performance status regardless of cytogenetic findings, supportive care alone was suggested. The authors point out that the life-threatening complications of t-AML are the result of persistent and profound cytopenias regardless of the fraction of myeloblasts accumulating in the marrow or circulating in the peripheral blood. This may be due to the persistence of the primary malignancy or, more likely, the consequence of prior therapy on hematopoietic reserve. Furthermore, many such patients have sustained prior treatment-associated immunosuppression that may have residual effects on immune competence and many also may have had sensitizing red cell or platelet transfusions.
Whether the prior chemotherapy or radiation has resulted in the emergence of chemotherapy-resistant leukemic stem cells remains a theoretic possibility.
Acknowledging that hematopoietic reserve is typically less in patients with t-AML, the administration of standard AML therapy is challenging. Nevertheless, allogeneic hematopoietic cell transplant (HCT) is an option, and in fact remains the best chance for prolonged survival. Yet, early deaths from regimen-related toxicity are more common in patients with t-AML, particularly in those who have been heavily pretreated or are of advanced age. Non-myeloablative, reduced-intensity, allogeneic HCT currently is under investigation for those patients who are ineligible for standard myeloablative HCT.
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