Lessons learned from therapy-related acute myeloid leukemia

In this issue of Haematologica, Nilsson and colleagues present the results of a large retrospective analysis of real-world data regarding the incidence and prognostic implications of therapy-related acute myeloid leukemia (t-AML, n=686) based on three Swedish nationwide population-based registries.¹ This methodology allows an unbiased view on prognostic implications and reliable observations of time trends in incidence. At the same time, this is one of the largest datasets investigating the clinical behavior of t-AML in comparison to de novo AML.

The authors report that during the study period, ranging from 1997-2015, the incidence of t-AML almost doubled with a yearly increase in t-AML of 4.5% (95% confidence interval: 2.8%-6.2%), most frequently due to t-AML after breast and prostate cancer. This is in part due to improvement of cancer treatments with decreased mortality during the same period, leading to better longterm survival after mutagenic cancer treatments.^2,3 It also points to the increasing likelihood of encountering these patients in clinical practice. Thus, a better knowledge of, as well as better treatment approaches for, these patients is needed.

Table 1.Outcomes of patients with therapy-related acute myeloid leukemia.

Secondly, the authors described the role of t-AML regarding prognosis within AML risk groups.⁴ Genetically, t-AML was underrepresented in patients with favorable risk, and overrepresented in patients with intermediate or adverse risk.⁵ Despite a good performance status (Eastern Cooperative Oncology Group score ≤2) patients with t-AML were less likely to receive intensive induction treatment (60% vs. 71%, P<0.001) and intensively treated patients were less likely to achieve complete remission (58% vs. 75%, P<0.001) as compared to those with de novo AML. The reason for the worse outcome of patients with intermediate- and poor-risk t-AML compared to their de novo counterparts, also when adjusting for other factors such as cytogenetics, age and performance status, is likely multifactorial. A higher frequency of unfavorable mutations and/or an enrichment of mutations originating from clonal hematopoiesis in patients with t-AML may contribute.^6,7

Allogeneic hematopoietic cell transplantation (HCT), regardless of disease state, was performed in 9% of the patients with t-AML as compared to 16% in those with de novo AML (P<0.001). Corresponding rates of allogeneic HCT in first remission were 7% in t-AML and 12% in de novo AML (P=0.002), with no increase or decrease of transplantation rates over time. In multivariable analysis, t-AML was associated with poorer outcome in cytogenetically intermediate- and adverse-risk AML, but 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. This suggests that t-AML patients with favorable-risk AML should be approached using the same treatment strategy as de novo favorable-risk patients and intensive chemotherapy including allogeneic HCT, if appropriate, should not be withheld from these patients. Biologically, this raises the question of whether t-AML with favorable risk (i.e., acute promyelocytic leukemia, NPM1 without FLT3-ITD and corebinding factor leukemias) are really therapy-related or more likely de novo AML. Comparative next-generation sequencing analysis may shed light on this issue.

Intermediate- and adverse-risk patients with t-AML have even poorer survival compared to their de novo counterparts. After allogeneic HCT, these patients suffer from high transplant-related mortality (Table 1), possibly reflecting cumulative toxicity of cancer treatment.⁵ However, the data should be interpreted with caution since relapses might be underreported, and thus the transplant-related mortality might be overestimated. Nevertheless, novel treatment approaches for these patients are highly warranted.⁸ In addition, since intensifying the conditioning regimen was identified as a risk factor for worse outcome, the most appropriate conditioning regimen remains to be established.⁹

More recently, new therapeutic options, targeting FLT3, IDH1/2 and BCL2 have become available¹⁰ and may have the potential to improve outcome in certain subtypes of t-AML.

Footnotes

• Received August 10, 2022
• Accepted August 19, 2022

Correspondence

S. Kayser s.kayser@dkfz-heidelberg.de

Disclosures

No conflicts of interest to disclose.