Big Jump in Therapy-Related AML Amid Growth in Population of Cancer Survivors

The incidence of therapy-related acute myeloid leukemia (tAML) increased gradually but steadily over the past three decades, a study from Japan showed.

The rate of tAML rose almost threefold, from 0.13 per 100,000 population in 1990 to 0.36 per 100,000 in 2020. The overall incidence of AML increased during the same period, but the rate of tAML as a proportion of total AML cases almost doubled. The overall prevalence of tAML was 6.5%.

AML related to cancer therapy occurred most often after treatment for other hematologic malignancies, but almost 15% of cases occurred after breast cancer, representing a “substantial” increase over the study period, reported Kenji Kishimoto, MD, PhD, of Osaka International Cancer Institute, and colleagues in Cancer.

“The present results suggest an emerging concern regarding the burden of tAML as a post-cancer therapy complication,” the authors concluded. “Findings from this study lay the foundation for further studies to elucidate the mechanisms of the change in tAML epidemiology.”

The growing use of cancer immunotherapy is expected to reduce treatment-related toxicity, but the impact on tAML remains unclear, the authors noted. A recent single-center study showed that treatment with immune checkpoint inhibitors was associated with a decreased incidence of second primary cancers.

“The study provides an important step towards better understanding how the nature of tAML is changing with the increasing number of cancer survivors,” noted Kishimoto in a press release.

‘Unfortunate Consequence’ of Success

The Japanese study is consistent with a recent registry-based study from Sweden, which showed a doubling of tAML incidence from 1997 to 2015, said Mikkael Sekeres, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami.

“Therapy-related acute myeloid leukemia arises in patients who have been treated with either chemotherapy or radiation therapy for other cancers,” Sekeres told MedPage Today. “As more patients get treated for their cancers, the rates of therapy-related myeloid neoplasms, such as acute myeloid leukemia or myelodysplastic syndromes, increase concomitantly.”

“When we see these increased rates, they reflect both better access to care for the treatment of primary cancers, and the efficacy of those treatments, as patients are now living long enough to develop secondary malignancies,” he said. “Furthermore, as people are living longer in the general population, they are more likely to develop secondary cancers.”

Therapy-related AML is an “unfortunate consequence of our great success in treating other cancers,” he added. “For example, for the first time, I saw patients in my clinic with therapy-related myeloid neoplasms who had been treated previously for their lung cancer.”

AML related to cancer therapy has been recognized as a distinct clinical entity for more than 40 years. Genetic mutations, preleukemic clonal hematopoiesis, and an abnormal microenvironment have been theorized as potential contributors to tAML pathogenesis, Kishimoto and colleagues noted.

The condition is a heterogeneous subtype of myeloid malignancy, and the latency period from cytotoxic exposure to tAML varies widely. It is associated with older age and unfavorable cytogenetics, which contribute to inferior treatment responses and worse survival as compared with de novo AML.

Population-based studies of tAML have yielded conflicting data regarding long-term trends. Available data have come primarily from Europe and North America, the authors said. Recent changes in cancer epidemiology might have an impact on the characteristics of patients with tAML, such as a decreasing incidence of gastric cancer in East Asia and increasing rates of newly diagnosed cancers in younger patients.

Adding to the Evidence Base

To add contemporary data to the evidence base for tAML, the authors examined trends in tAML as reflected in the Osaka Cancer Registry for the years 1990 to 2020. The primary outcome was incidence of tAML, with distribution of primary cancers as the key secondary outcome.

The investigators identified 9,841 cases of AML, including 636 (6.5%) cases of tAML. Patients with tAML were older at diagnosis (69 vs 66 for de novo AML, P<0.001), and significantly more patients with tAML were in the 60-74 age group (46.5% vs 35.0%, P<0.001). Women accounted for a higher proportion of patients with tAML (45.0% vs 39.5%, P=0.007).

The primary finding was a near-tripling of tAML incidence over the study period. The incidence of overall AML increased during the three decades (3.18 to 4.37 per 100,000 population), but the incidence of tAML as a proportion of total AML increased even more, from 4.4% during 1990-1999 to 5.6% during 2000-2009 to 8.2% during 2010-2020.

The primary cancers most often associated with tAML were other hematologic malignancies (23.1%), followed by breast cancer (14.6%), colorectal cancer (11.5%), and gastric cancer (8.7%). Lymphoma accounted for a majority of the primary hematologic malignancies. Therapy-related AML after primary solid tumors occurred more often in patients 45 or older (P<0.001).

The distribution of primary cancers associated with tAML changed over time. Gastric cancer was the second most common primary cancer during 1990-1999 but had a decreasing trend thereafter. Breast cancer emerged as a prominent primary cancer during 2000-2009, and lung and head and neck cancers accounted for a major share of primary cancers during 2010-2020.

Median age at tAML diagnosis increased from 66 during 1990-1999 to 71 during 2010-2020, as did median age at diagnosis of primary cancer (60 during 1990-1999 to 64 during 2010-2020, P=0.007). The median latency period from primary cancer to tAML diagnosis was 5 years, with relatively longer latency times for primary gastric, bladder, and cervical cancers.