Gonadal function and fertility preservation in girls with Hodgkin lymphoma treated according to the EURONET-PHL-C2 Protocol: the fertility add-on study

Abstract Study question What is the gonadotoxic potential of the EURONET-PHL-C2 treatment protocol for female childhood Hodgkin lymphoma patients, and how frequently are co-treatments to preserve fertility applied? Summary answer Treatment-induced amenorrhea (72%) persisted in > 10% of cases. Results on AMH are available by April 2023. Fertility preserving (co-)treatments were applied in 27% of patients. What is known already Current treatment for childhood Hodgkin lymphoma (HL) is highly effective with survival rates exceeding 90%. However, HL treatment affects gonadal function and HL survivors were proven to be at risk of premature ovarian insufficiency. In effort to reduce late effects, treatment protocols were adapted and toxic procarbazine was successfully omitted. The current EuroNET-PHL-C2 protocol aims to reduce use of radiotherapy by intensifying chemotherapy. The cumulative dose of cyclophosphamide is increased by 25% in the intensified treatment-arm, the impact of this change in therapeutic protocol on gonadal function is currently unknown. Therefore, a fertility study was incorporated in the EuroNET-PHL-C2 study. Study design, size, duration This international, prospective, multicenter cohort study is embedded in the EuroNET-PHL-C2 study, an European phase-3 treatment study evaluating the effectivity of HL treatment with OEPA-COPDAC (OEPA: vincristine sulfate (oncovin), etoposide, prednisolone and doxorubicin (adriamycin); COPDAC: cyclophosphamide, vincristine sulfate (oncovin), prednisone and dacarbazine) versus OEPA-DECOPDAC (DECOPDAC: COPDAC with additional doxorubicin and etoposide) in a randomized setting. In the present fertility add-on study, 205 (104 girls, 101 boys) patients were included between January 2017 and September 2021. Participants/materials, setting, methods Female patients, aged <18 years, treated according to the EuroNet-PHL-C2 protocol for classical HL, were recruited across 18 sites (the Netherlands, Belgium, Germany, Austria, Czech Republic). All parents and patients (aged ≥12 years old) provided written informed consent. Serum AMH levels and menstrual cycle were evaluated over time (at diagnosis, during- and directly after treatment, 2 years post-diagnosis) and compared between OEPA-COPDAC and OEPA-DECOPDAC treatment groups. Moreover, use of available fertility preservation treatments was evaluated. Main results and the role of chance In the present analysis, 100 girls were included of whom 88 completed 2 years of follow up. Median age at diagnosis was 15 years (7-18), 8 girls were prepubertal and 92 post pubertal (87% postmenarchal). 17 girls were diagnosed at an early stage of HL (TL1) and 83 in more advanced stages (TL2/TL3, 66% received COPDAC and 33% DECOPDAC). 5 patients (5%) were irradiated in the pelvic area. Of the 46 postmenarchal girls who did not receive hormonal contraceptives during treatment, 33 (72%) experienced treatment-induced amenorrhea, at least 4 (12%) had persisting amenorrhea at 2 years post-diagnosis. 4 girls (22%) who stopped taking hormonal contraceptives after treatment had no (return of) spontaneous cycle. 2 girls (2%) underwent ovariopexy. 4 girls cryopreserved oocytes before treatment and 12 cryopreserved ovarian tissue (OTC). 15 (15%) received GnRH analogues as a co-treatment. Data on AMH-levels up to 2 years post-diagnosis will be available by April 2023. Change in AMH will be evaluated, comparing number of received chemotherapy-cycles (3/4/6), DECOPDAC versus COPDAC and pubertal stage at time of diagnosis. Additional analyses will be performed to assess the impact of applied fertility preservation methods on gonadal function (i.e. AMH levels after OTC or receiving GnRH agonist). Limitations, reasons for caution The current analysis included data up to 2 years post-diagnosis. Potential recovery or late emerging effects of treatment remain unknown. The studied population comprises young girls with diagnosis of HL often concurring with pubertal transition, during which AMH levels naturally rise. SD z-scored will be used to analyze AMH results. Wider implications of the findings The fertility add-on study is the first study to prospectively evaluate reproductive markers in children treated for HL. Study results are highly valuable to determine effect of the proposed new treatment regimen for childhood HL on fertility . Trial registration number Clinicaltrials NCT02684708; EudraCT number 2012-004053-88