Dr van der Straten Discusses the Risk for SPMs in CLL

In an interview with Lina van der Straten, MD, PhD, the Department of Research and Development of the Netherlands Comprehensive Cancer Organisation, the Department of Internal Medicine of the Albert Schweitzer Hospital, and the Department of immunology of the Erasmus MC, Rotterdam, Netherlands, spoke on the findings and significance of a nationwide, population-based study on the risk of second primary malignancy (SPM) development in chronic lymphocytic leukemia (CLL) patients.

What existing data led you and your co-investigators to conduct this research?

The survival of patients with CLL at the population level improved dramatically over the past decades due to more efficacious therapies in the upfront and relapsed/refractory (R/R) setting.

The downside of this improved longevity is the development of SPMs, which, in turn, may contribute to morbidity and excess mortality in CLL patients.

Therefore, awareness of the magnitude of SPMs in CLL is essential for health-related planning and surveillance activities. As such, in this nationwide, population-based study we assessed the risk of SPM development in CLL patients diagnosed in the Netherlands as compared to the general Dutch population.

Please briefly describe your study and its findings. Were any of the outcomes particularly surprising?

From 1989 until 2018 we selected 23,622 CLL patients from the Netherlands Cancer Registry of whom 4,062 (17%) subsequently developed an SPM after a median follow-up time of 4 years.

To counteract surveillance bias, an SPM was defined as a malignancy occurring at least 6 months after CLL diagnosis. In addition, transformations were regarded as the same entity as the primary tumor and basal cell carcinomas were excluded from the analysis.

Overall, the risk of SPMs in CLL was 64% higher as compared to the general population (standardized incidence rate [SIR], 1.64). This increased risk was observed both for solid (SIR, 1.72) and hematological (SIR, 1.11) malignancies with no sex-related differences. Patients aged 18-60 years were more at risk for the development of an SPM (SIR, 1.88) as compared to their elderly counterparts >60 years (SIR, 1.58).

The overall risk was significantly heightened for the following sites (in order of increasing risk): skin (squamous cell and melanoma), kidney and renal, primary site unknown, lung, colon and rectum, and prostate. As for hematological malignancies, the risk of developing acute myeloid leukemia (AML) was significantly increased compared to the general population. Conversely, myeloproliferative neoplasms (MPNs) were less frequently observed than in the general population.

What are the possible real-world applications of these findings in clinical practice?

In this nationwide, population-based study, we demonstrated that CLL patients in the Netherlands have an increased risk of developing various SPMs compared to the general population.

SPMs in CLL may originate from shared pathophysiological factors, environmental exposures, host characteristics, or some combination of the 3. In addition, CLL-related therapy could have attributed to the development of an SPM, particularly in AML.

Collectively, our study findings contribute to the awareness of the risk of SPMs in CLL. This information could contribute to the treatment-decision making of the physician.

Although the risk of an SPM is heightened in CLL patients, the absolute excess risk (AER) per SPM remains low. However, SPMs of the skin had the largest AER of 78 per 10,000 for squamous skin carcinomas and 12 per 10,000 for melanoma.

As such, surveillance activities such as a regular check-up by the dermatologist could be considered. Moreover, the current study also serves as a benchmark to assess how the spectrum of SPMs may alter in a contemporary era with an increased application of targeted therapies.

Do you and your co-investigators intend to expand upon this research? If so, what are/will be your next steps?

Yes, we want to perform some additional analysis to evaluate whether the risk of development of an SPM could also be established the other way around.

The aim of this analysis would be to distinguish between shared pathological factors of the SPM and the CLL, and specific features of the disease itself such as immune dysfunction and treatment exposure.

Furthermore, we will apply this statistical method to other hematological malignancies within the Netherlands Cancer Registry.

van der Straten L, Levin MD, Dinnessen M, et al. Second Primary Malignancies in Patients With Chronic Lymphocytic Leukemia: A Nationwide, Population-Based Study in the Netherlands. Presented at: EHA2021 Virtual Congress; June 9, 2021; virtual. Abstract EP637.