Fertility Rates in Young Hodgkin Lymphoma Survivors: A Danish Nationwide Cohort Study of 769 Patients
Authors: Øvlisen Andreas Kiesbye , Jakobsen Lasse H. , Kragholm Kristian Hay , Hutchings Martin , Frederiksen Henrik , Kamper Peter , Eloranta Sandra , Weibull Caroline , Glimelius Ingrid , Ekstroem Smedby Karin Ekstrom , Severinsen Marianne Tang , El-Galaly Tarec Christoffer C. 
Published: November 2019

Introduction: The vast majority of young adults with Hodgkin lymphoma (HL) are cured by contemporary first line treatments. Treatment-related long-term toxicities can have a negative impact on survivorship and the risk of infertility may be particularly pertinent to young HL survivors. This study aimed to investigate the fertility rate (rate of first child after index date) over time in patients with HL compared to the matched controls.
Methods: All Danish patients with HL, including classical and lymphocyte predominant HL, diagnosed in the period 2000-2015 were identified in the Danish Lymphoma Registry. Patients aged 18-40 years at diagnosis with documented complete remission after first line therapy were included. Patient data were merged with the Danish Fertility Database and the Medical Register of Births and Deaths. For each HL patient, five random Danish citizens alive at the index date of the HL patient were matched on birth date, sex, and parenthood status (categorical; with children vs without children at the index date). Follow-up was measured from 9 months post diagnosis (index date) until the time of first child, relapse, death, or censoring, whichever came first. Patients with progression/relapse within the first 9 months after diagnosis were excluded. Cumulative incidences of first living child after the index date were computed for the entire cohort and stratified on sex using the Aalen-Johansen estimator with death or relapse before first child after index date as competing events. Cox regression was used to compare the rates of first child of HL patients and matched controls by clinical subgroups and estimated for males and females separately.
Results: A total of 769 HL patients were included (male:female ratio 1.2, median age 30 years) and median follow-up was 9.9 years. The mean numbers of children per person at start of follow-up were similar in patients and matched controls (female HL patients 0.64 vs matched controls 0.63 children per individual; male HL patients 0.56 vs matched controls 0.54 children per individual). At the end of follow-up, average numbers of children were higher in male and female HL patients (female HL patients 1.22 children per individual; matched control 1.14 children per individual) and males (HL patients 1.00 children per individual; matched controls 0.92 children per individual). The cumulative incidence of first child after index date in female HL patients was lower during the first three years of follow-up compared to the matched controls. However, beyond three years of follow-up the cumulative incidences of first child after index date were similar (Figure 1A). Among male HL patients the cumulative incidence of first child after index date was higher than that of the matched controls throughout the entire follow-up (Figure 1B). Overall, fertility rates were higher in HL patients (males, 36.7 per 1,000 person years; females, 41.7 per 1,000 person years) as compared to the matched controls (males, 24.2 per 1,000 person years; females, 33.0 per 1,000 person years). The Cox regression showed that both male and female patients with HL had higher fertility rates as compared to matched controls (males, HR 1.5, p-value < 0.001; females, HR 1.2, p-value = 0.012; Table 1). This was also observed in specific clinical subgroups, i.e. ages 18-30 years, CCI 0, no children prior to diagnosis, and limited stage disease. Moreover, among patients receiving 6+ cycles of chemotherapy, fertility rates were not lower than expected (Table 1).
Conclusion: The fertility rates for long-term HL survivors without progression/relapse were higher than in matched controls, in particular for male HL patients. Elevated fertility rates as compared to the matched controls were observed for lower age (<30 years), limited stage disease, and for patients without children at the time of diagnosis. No clinical subgroup did significantly decrease the fertility rates.

Disclosures
Hutchings: Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Novartis: Research Funding. Frederiksen:Abbvie: Research Funding; Alexion: Research Funding; Gilead: Research Funding; Novartis: Research Funding; Janssen: Research Funding. Eloranta:Karolinska Institutet: Other: coordinator for a public-private real world evidence; Janssen Pharmaceuticals.: Other: project coordinator for a public-private real world evidence. Glimelius:Janssen Pharmaceuticals: Honoraria. Ekstroem Smedby:Janssen Cilag: Honoraria, Other: Grant funding, Research Funding; Celgene: Honoraria, Other: Grant funding, Research Funding; Takeda: Honoraria, Other: Grant funding, Research Funding. El-Galaly:Roche: Employment, Other: Travel support; Takeda: Other: Travel support.