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Use of high-dose chemotherapy and autologous hematopoietic stem-cell transplantation (HSCT) for patients with aggressive lymphoma was associated with an increased risk of certain second primary malignancies (SPMs), according to a retrospective Danish population-based cohort study.

The overall SPM rate was higher among lymphoma patients compared with matched controls from the general population (HR 2.35, 95% CI 1.93-2.87, P<0.0001), reported Trine Trab, MD, of Copenhagen University Hospital, and colleagues.

Specifically, lymphoma patients had an increased risk of non-melanoma skin cancer (HR 2.94, 95% CI 2.10-4.11, P<0.0001) and myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML; HR 41.13, 95% CI 15.77-107.30, P<0.0001) compared with matched controls, they wrote in .

However, there was no significant difference in the risk of solid tumors (HR 1.21, 95% CI 0.89-1.64, P=0.24).

"Our findings are of clinical importance when comparing the risks and benefits for patients with lymphoma who are being considered for high-dose chemotherapy and autologous HSCT, and for making the best-informed treatment decisions when alternative treatment options are available," Trab and colleagues noted.

In a , Anna Sureda, MD, PhD, and Eva Domingo-Domenech, MD, both of the University of Barcelona, wrote that the development of SPMs after HSCT "emphasizes the importance of balancing between achieving remission and minimizing the risk of long-term complications."

Although HSCT offers the possibility of cure for patients with aggressive lymphomas who have relapsed after initial therapies, "the potential for SPMs highlights the need for careful consideration of other treatment options," they added.

Trab and colleagues reported that the 5-, 10-, and 15-year cumulative risks of first SPMs among patients treated with high-dose chemotherapy and autologous HSCT were 12%, 20%, and 24%, respectively, while the corresponding cumulative risks in matched controls were 7%, 14%, and 21%.

Meanwhile, the 15-year cumulative risk of non-melanoma skin cancer was 8% for lymphoma patients versus 7% for matched controls, while the 15-year cumulative risks of MDS or AML were 5% versus 0.3%, respectively.

The 5-, 10-, and 15-year cumulative risks of any solid tumors were 4%, 7%, and 9% in lymphoma patients compared with 4%, 9%, and 13% in matched controls.

In their editorial, Sureda and Domingo-Domenech said the results of this study should be considered in the context of the development of new -- and potentially curative -- treatments for lymphoma, such as chimeric antigen receptor (CAR) T-cell therapy.

"The specificity of [CAR T-cell] therapy reduces damage to healthy cells that are associated with conventional treatments," they wrote. "[D]espite little data regarding the development of SPMs due to the small number of patients who have been treated and short follow-up, development of SPMs does not appear to be a substantial side-effect with this therapeutic strategy."

For this study, Trab and colleagues included 803 patients from the Danish Lymphoma Registry with an aggressive lymphoma who received high-dose chemotherapy and autologous HSCT from January 2001 through December 2017. They were matched 1:5 to 4,015 controls from the Danish Civil Registration System.

About two-thirds of the participants in each group were men, and the median age in both groups was 57 years. Of the patients with lymphoma, 34% had diffuse large B-cell lymphoma, 29% had mantle cell lymphoma, 21% had peripheral T-cell lymphoma, and 15% had Hodgkin lymphoma. Most patients received one line of chemotherapy before high-dose chemotherapy and autologous HSCT. Median follow-up was 7.76 years.

The authors acknowledged several limitations to their study, including the lack of lifestyle data available, as well as data on genetic factors associated with cancer.

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