Reproduktiv Patterns Among Non-Hodgkin Lymphoma Survivors By Subtype in Sweden, Denmark and Norway

Background Studies concerning reproductive patterns among non-Hodgkin lymphoma (NHL) survivors are scarce and those available have reported conflicting results. Until today, no study has reported reproduction rates for different NHL subtypes despite that treatment regimens and disease activity vary considerably between aggressive and indolent NHL. Hence, research disentangling reproductive patterns of NHL patients by subtype are warranted.

Methods In this matched cohort study we identified all NHL patients in Sweden, Denmark, and the south-east health region in Norway who were diagnosed in 2000-2019 and aged 18-40 years at diagnosis. Patients were identified from the Swedish and Danish lymphoma registers, and the clinical data base at Oslo University Hospital. NHLs were categorised according to clinical behaviour as aggressive or indolent, and by histological characteristic as diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), T-NK cell lymphoma and other B-cell lymphomas. Population comparators were matched to each patient on sex, birth year, and country in a 1:10 ratio in Sweden and Denmark, and a 1:5 ratio in Norway. Data on childbirths was obtained from national medical birth registers. Patients and comparators were followed from 9 months after index date (diagnosis or matching date) until date of first childbirth, death, or administrative censoring (December 2017, 2018, or 2019 for Norway, Sweden, and Denmark, respectively, or after 10 years of follow-up). Hazard ratios (HRs) contrasting clinical and histological NHL subtypes to comparators were estimated using Cox regression within time bands allowing for non-proportional hazards. Flexible parametric survival models were used to estimate cause-specific cumulative incidence (CIF) of childbirth, in the presence of death as a competing event, and differences thereof (ΔCIF). A comprehensive analysis plan has been pre-registered on the Open Science Framework (DOI: 10.17605/OSF.IO/A4U3D).

Results We included 2,212 NHL patients and 20,709 comparators. Most patients were diagnosed with an aggressive lymphoma (67.9%). The most common histological subtypes were DLBCL (49.2%) and FL (19.4%). Among patients with aggressive and indolent lymphoma, 21.5% and 10.6% were aged between 18 and 25 years at diagnosis, respectively. Results stratified by clinical aggressiveness showed that males and females diagnosed with aggressive lymphoma subtypes had lower reproduction rates than comparators the first 3 years after diagnosis (HR_female: 0.44, 95% CI:0.32; 0.61, HR_male :0.63, 95% CI: 0.49; 0.81), whereas reproduction patterns among survivors with indolent lymphomas were similar to comparators within the first 3 years after diagnosis among both males and females (HR_female: 0.68, 95% CI:0.46; 1.00, HR_male: 0.91, 95% CI: 0.67; 1.23). When stratifying by histological subtypes both male and female DLBCL patients had lower reproduction rates the first 3 years after diagnosis (HR_female: 0.44, 95% CI: 0.30; 0.63, HR_male: 0.63, 95% CI: 0.48; 0.85). Among females, those diagnosed with T-NK cell lymphoma and other B-cell lymphomas showed similar decreases (HR_{T-NK cell}: 0.52, 95% CI: 0.28; 0.96; HR_{Other B-cell}: 0.50, 95% CI: 0.26; 0.98). After 3 years reproduction rates of NHL patients reached those of comparators, for both levels of aggressiveness and all histological subtypes. Nevertheless, when contrasted to comparators, the proportion of survivors who had at least one childbirth during follow-up was decreased up to 10 years after diagnosis among individuals with a previous aggressive lymphoma (ΔCIF_female: -0.06, 95% CI: -0.10; -0.01; ΔCIF_male: -0.04, 95% CI -0.08; -0.00) and those with previous DLBCL (ΔCIF_female: -0.07, 95% CI -0.11; -0.02; ΔCIF_male: -0.06, 95% CI -0.10; -0.02) (Figure 1).

Conclusion Patients with indolent lymphomas have reproductive patterns similar to the general population. Patients with aggressive lymphomas showed decreased reproduction mainly the first years following diagnosis. Nevertheless, the reduced CIF indicates that patients with DLBCL do not reach the reproduction level of comparators even after 10 years. Fertility counselling is therefore particularly important for this patient group.

Figure 1 Cause-specific CIF of childbirth across time since diagnosis in the presence of death as competing event among cases and comparators (bottom lines) and differences thereof (ΔCIF) (top line).

Weibull:Red Door Analytics: Membership on an entity's Board of Directors or advisory committees; Janseen Cilag: Research Funding; War On Cancer: Current Employment. Smedby:Janseen Cilag: Research Funding. Jakobsen:Roche: Honoraria. Glimelius:Takeda: Research Funding; Janseen Cilag: Research Funding. Larsen:Genentech: Research Funding; Roche: Consultancy; Novartis: Consultancy; Gilead Sciences: Consultancy; Bristol Myers Squibb: Consultancy. Holte:Nordic Nanovector: Honoraria, Other: Safety committee; Novartis: Honoraria, Other: Advisory board; Gilead: Honoraria, Other: Advisory board; Incyte: Honoraria, Other: Advisory board; Takeda: Honoraria, Other: Advisory board; Genmab: Honoraria, Other: Safety committee. El-Galaly:Abbvie: Other: Teaching in 2021; Roche: Ended employment in the past 24 months. Eloranta:Janseen Cilag: Research Funding.