Survival in Mantle Cell Lymphoma Patients with a Second Primary Malignancy
Authors: Abalo Kossi D , Trap Trine , Baech Joachim , Ekberg Sara , Pahnke Simon , Albertsson-Lindblad Alexandra , Ekstroem Smedby Karin , Jerkeman Mats , Brown Peter , Larsen Thomas Stauffer , Gronbaek Kirsten , El-Galaly Tarec Christoffer , Glimelius Ingrid 
Published: December 2024

Background
One of the most detrimental late effects after treatment of lymphoma is second primary malignancies (SPM). We recently showed an increased risk of SPMs in two large population-based studies in Sweden1 and Denmark2. The aim of the current study was to investigate the impact of SPMs on survival for patients with mantle cell lymphoma (MCL) relative to comparators with a similar malignancy.
Methods
All patients diagnosed with MCL in Denmark in 2000-2020 and Sweden in 2000-2017 with a SPM after the MCL diagnosis were included. Patients were matched with individuals from the background population (comparators) without lymphoma who had a similar malignancy as the index patient. Matching was done in a ratio of 1:5 on birth year, sex, malignancy ICD10-code, and calendar year of malignancy. Both patients and comparators were followed from diagnosis of the SPM/malignancy until death, emigration, or 31st December 2021 (2019 in Sweden). Overall survival (OS) was calculated for patients and comparators using the Kaplan Meier estimator and stratified by SPM type. Adjusted all-cause mortality hazard ratios (HR) with 95% confidence intervals (CI) were calculated with adjustment for age, sex, and year of SPM/malignancy. Descriptive statistics were reported using the averaged value from both countries and the all-cause mortality HRs were summarized to estimate pooled hazard ratios (pHR) combining both countries using the inverse variance weighted method with a random effect.
Results
In total, 497 patients with a SPM after MCL and 1,992 matched comparators with similar malignancies without lymphoma were followed for a median of 4.7 years (patients) and 4.8 years (comparators). The majority of patients had stage IV MCL (71.5%) and intermediate or high MCL international prognostic index (76.9%) at MCL diagnosis. MCL first line treatment was chemoimmunotherapy (80%) and only 8% received radiotherapy in both countries. Patients had a median age of 75 years at SPM diagnosis.
The most common SPMs were skin cancer (45%), gastrointestinal cancer (12%), prostate cancer (12%), and lung cancer (12%). Secondary acute myeloid leukemias (AML) or myelodysplastic syndrome (MDS) were seen in 18 patients, accounting for 4% of all SPMs. A total of 127 (54%) and 155 (59%) patients died during follow-up in Denmark and Sweden, respectively. Among the 155 deaths in Sweden, 38% died from MCL, 24% died from solid cancer, 20% from other causes than malignancy, 13% from secondary leukemia/MDS and 5% from skin cancer. In patients from Sweden with skin cancer, the leading cause of death was MCL (46%) and only a few (7%) died from the secondary skin cancer. Patients had a higher risk of dying than comparators with median OS of 4.3 years in Denmark and 2.7 years in Sweden versus 6.8 and 9.1 years for comparators, respectively, and pHR for all-cause mortality of 2.0 (1.1-3.6). In both countries, elevated all-cause mortality rates were seen for patients with skin SPMs pHR 2.8 (1.8-4.5), MDS/AML SPMs pHR 2.4 (1.3-4.3), and a trend was seen towards increased mortality rate for solid SPMs pHR 1.4 (0.8-2.5). In Sweden, the median OS after solid cancers, skin cancers, and MDS/AML for patients were 4.1 years, 2.5 years, and 4.4 months compared to 10.4 years, 8.2 years, and 19.7 months for comparators. Among skin SPM patients, the median OS for melanoma (N=14) was 4.0 years and for non-melanoma (N=95) was 2.5 years. In Denmark, the median OS after solid cancers, skin cancers, and MDS/AML patients were 2.2 years, 6.1 years, and 10.1 months compared to 3.0 years, 12.6 years, and 21.6 months for comparators. Among skin SPM patients in Denmark, 99 were non-melanomas (with a median OS: 6.1 years) and 15 were melanomas.
Conclusions
Patients with MCL with a SPM have a compromised survival when compared to a background population with similar malignancies. The most common SPMs were skin cancers, which was associated with a higher likelihood of death, mostly driven by the underlying MCL.
References Abalo KD et al. Secondary malignancies among mantle cell lymphoma patients. Eur J Cancer Oxf Engl 1990. 2023 Trab T et al. Second primary malignancies in patients with lymphoma in Denmark after high-dose chemotherapy and autologous haematopoietic stem-cell transplantation Lancet Haematol. 2023