Risk of second primary malignancies in patients with chronic lymphocytic leukemia: a population-based study in the Netherlands, 1989-2019

Abstract

The longevity of patients with chronic lymphocytic leukemia (CLL) has improved progressively over the past decades, making it essential to understand long-term health outcomes, such as second primary malignancies (SPMs). Therefore, this nationwide, population-based study assessed the risk of SPM development in CLL patients diagnosed during 1989-2019 in the Netherlands compared to the expected number of malignancies in an age-, sex-, and period-matched group from the general Dutch population. In 24,815 CLL patients followed for 162,698.49 person-years, 4369 SPMs were diagnosed with a standardized incidence ratio (SIR) of 1.63 (95% confidence interval [CI] 1.59–1.68). This elevated risk was observed for solid (SIR, 1.67; 95% CI, 1.65–1.75) and hematological SPMs (SIR 1.42; 95% CI, 1.24–1.62). The highest risk for SPMs was noted beyond five years post-diagnosis (SIR, 1.70; 95% CI, 1.62–1.77), for male individuals (SIR, 1.70; 95% CI, 1.64–1.77), and patients aged 18–69 years (SIR, 1.92; 95% CI, 1.79–2.05). The risk of SPMs was higher in CLL patients who received anti-neoplastic therapy (SIR, 2.12; 95% CI, 1.96–2.28), as compared with those who did not (SIR, 1.58; 95% CI, 1.53–1.63). Routine surveillance activities and tailored interventions to counteract the increased morbidity and excess mortality associated with SPMs are essential for improving long-term outcomes in CLL patients.

A population level analysis of second hematological malignancies in chronic lymphocytic leukemia/small lymphocytic lymphoma survivors in the era of targeted therapies

“…27,28 We assessed the association between 5-year-periods of CLL A multivariate analysis revealed increased risk of SHM in CLL patients with male sex, younger age at diagnosis, and exposure to chemotherapy, consistent with prior studies. 13,16,21 In alignment with prior studies, we noted development of SHM significantly reduces OS in CLL patients (OS: 99 vs. 127 months). 11,12,29 Among myeloid SHM, CML (95 months) had the best while de-novo AML (63 months) had the poorest median OS after CLL diagnosis, a finding consistent with prior studies.…”

“…The risk is higher compared to that reported in prior studies, perhaps due to relatively recent period of CLL diagnosis (year 2000 onwards) included in our study than the prior studies (year 1973 onwards). 13,21 There has been a paradigm shift in treatment for CLL in this period and there is a growing concern for associated increment in second aggressive malignancies. During this period studies have reported higher risk of SHM in CLL survivors, partly attributable to fludarabine-based chemotherapies.…”

“…11 An Australian study reported that 12% (61/517) of CLL patients developed SHM (predominantly RT to DLBCL) after a median follow-up of 11-year 12 Recently, population-based study from Netherland, reported 42% higher risk of any SHM in CLL survivors, particularly 175% greater risk of AML, compared to general population. 13 In the US, studies on incidence and outcomes of second malignancies among CLL survivors are mostly limited to periods of conventional chemotherapies or chemo-immunotherapies. 7,14,15 It has been noted that there is an increased incidence of second malignancies (particularly MDS and AML) with treatments using fludarabine.…”

“…Notably, the median survival after SHM was significantly lower in patients who received prior treatment for CLL 11 . An Australian study reported that 12% (61/517) of CLL patients (1981–2020) developed SHM (predominantly RT to DLBCL) after a median follow‐up of 11‐year 12 Recently, population‐based study from Netherland, reported 42% higher risk of any SHM in CLL survivors, particularly 175% greater risk of AML, compared to general population 13 . In the US, studies on incidence and outcomes of second malignancies among CLL survivors are mostly limited to periods of conventional chemotherapies or chemo‐immunotherapies 7,14,15 .…”

Cutaneous Squamous Cell Carcinoma in Immunocompromised Patients—A Comparison between Different Immunomodulating Conditions

“…It is associated with significant immunosuppression, which is thought to increase the risk for second primary neoplasms. Van der Straten, et al [ 12 ] reported an increase of more than two-fold in the risk for secondary cSCC among 25,000 CLL patients, compared to the general population. Patients with CLL also exhibit an eight-fold increased risk for non-melanoma skin cancers compared to the general population [ 13 ].…”