Characterization of therapy-related acute myeloid leukemia: increasing incidence and prognostic implications

Abstract

Studies of therapy-related AML (t-AML) are usually performed in selected cohorts and reliable incidence rates are lacking. In this study, we characterized, defined the incidence over time and studied prognostic implications in all t-AML patients diagnosed in Sweden between 1997 and 2015. Data were retrieved from nationwide population-based registries. In total, 6,779 AML patients were included in the study, of whom 686 (10%) had t-AML. The median age for t-AML was 71 years and 392 (57%) patients were females. During the study period, the incidence of t-AML almost doubled with a yearly increase in t-AML of 4.5% (95% confidence interval: 2.8%-6.2%), which contributed significantly to the general increase in AML incidence over the study period. t-AML solidly constituted over 10% of all AML cases during the later period of the study. Primary diagnoses with the largest increase in incidence and decrease in mortality rate during the study period (i.e., breast and prostate cancer) contributed significantly to the increased incidence of t-AML. In multivariable analysis, t-AML was associated with poorer outcome in cytogenetically intermediate- and adverse-risk cases but t-AML had no significant impact on outcome in favorable-risk AML, including core binding leukemias, acute promyelocytic leukemia and AML with mutated NPM1 without FLT3-ITD. We conclude that there is a strong increase in incidence in t-AML over time and that t-AML constitutes a successively larger proportion of the AML cases. Furthermore, we conclude that t-AML confers a poor prognosis in cytogenetically intermediate- and adverse-risk, but not in favorable-risk AML.

Figure 1.

Incidence rates and proportion of therapy-related acute myeloid leukemias. (A) Age-standardized incidence rates of therapy-related acute myeloid leukemia (AML) and de novo AML. (B) Percentage of therapy-related AML cases of all AML cases. Figures show linear regression lines with 95% confidence intervals for visual aid.

Figure 2.

Primary diagnosis, gender, latency times and survival in therapy-related acute myeloid leukemia. (A) Number of cases and gender based on primary diagnoses. (B) Latencies between diagnosis of the primary disease and acute myeloid leukemia related to different primary diagnoses. (C) Median overall survival in intensively treated patients and overall in therapy-related acute myeloid leukemia grouped by primary disease. AML: acute myeloid leukemia; t-AML: therapy-related acute myeloid leukemia; Nineteen percent (n=133) of t-AML patients had more than one tumor diagnosis before the onset of t-AML, either occurring before, or more often after the malignancy for which the first chemotherapy and/or radiation therapy was given. Figure 3 displays in detail the complexity of sequential relations between the different diagnoses. Seventeen percent (n=118) of the patients had a diagnosis of MDS between the primary disease and t-AML.

Figure 3.

Paths to therapy-related acute myeloid leukemia. The figure shows the sequence of diagnoses of all malignant and/or hematologic diseases preceding the diagnosis of therapy-related acute myeloid leukemia (t-AML). Squares denote the primary disease for which cytotoxic treatment was given and ovals denote additional diseases, either prior to the primary disease or between the primary disease and t-AML. Numbers between squares and ovals represent number of cases. Twenty-eight cases for which the order of the disease could not be determined were excluded from the figure. MDS: myelodysplastic syndromes; MPN: myeloproliferative neoplasms.

Figure 4.

Survival in patients with therapy-related acute myeloid leukemia based on NPM1 and FLT3-ITD status. Overall survival by (A) FLT3-ITD status, (B) NPM1 mutational status and (C) FLT3-ITD/NPM1 status in therapy-related acute myeloid leukemia (t-AML). (D) Comparison of overall survival between t-AML and de novo acute myeloid leukemia (AML) in patients with NPM1^mut/F LT 3-ITD^absent.