CURRENT KNOWLEDGE ON FERTILITY AND HL CHEMOTHERAPY
The risk of infertility depends on patient’s age, type, and dose of chemotherapy.23–28 The risk of infertility is higher after the age of 30, as the follicle reserve diminishes with age.29–33 A large Norwegian study enrolled women diagnosed with and treated for HL, and reported that patients aged under 25 years had the same risk of infertility as the patients older than 30 years, but with delayed complications (15 vs 2 years).34
In men, spermatogonia is constant throughout life.35 In a recent study by the European Organization for Research and Treatment of Cancer Lymphoma Group (EORTC) and Groupe d’Etude des Lymphomes de l’Adultes (GELA), risk factors associated with infertility in men treated for HL were considered to be the general symptoms at diagnosis, especially fever and night sweats, and an increased erythrocyte sedimentation rate (ESR), probably due to proinflammatory cytokines.36
Early stage HL is treated with the ABVD (doxorubicine, bleomycin, vinblastine, dacarbazine) protocol as the standard-of-care.37,38 Hodgson et al,39 as well as Brusamolino et al,40 have shown that ABVD chemotherapy is safe and birth rates are comparable with the general population. Escalated BEACOPP (bleomycine, etoposide, doxorubicine, cyclophosphamide, vincristine, procarbazine, prednisone) protocol is used for advanced stage HL, which, according to a multivariate analysis of a German cohort, is positively associated with the development of consequent infertility.41 Similar results were later reported by Decanter et al,42 a group that correlated a decrease in the serum levels of anti-Müllerian hormone (AMH) in patients treated with both ABVD and alkylating agents-containing regimens, but the recovery was complete after 1 year in the ABVD group.42 The alkylating agent cyclophosphamide is known to have a high risk of gonadotoxicity.43 Cyclophosphamide alters the ovarian reserve in a dose-, duration-, and age-dependent manner; 40% of female patients under the age of 40 years have developed chDOR after cyclophosphamide-based chemotherapy regimens. Alkylating agents induce a risk of infertility of 3.98 when compared to the general population, with the risk increasing due to the cumulative dose.44,45
For men treated with the ABVD protocol, the recovery of spermatogenesis is similar with the recovery of ovarian function in women, 6–18 months following the end of therapy. van der Kaaij et al36 report a recovery time for the follicle-stimulating hormone (FSH) of 18 months for 82% of male patients treated without alkylating agents vs 27 months for 30% of patients treated with alkylating agent-containing regimens.36 As in female patients, alkylating agents and platinum-based regimens are the most important risk factor for infertility in men, with the risk being dose-dependent. The decline in sperm count was reported after 2–3 months of chemotherapy. The corticosteroids included in the escalated BEACOPP regimen also have an inhibitor effect on the hypothalamic–pituitary–gonadal axis of male patients.46,47
An additional risk factor for therapy-related infertility is pelvic radiotherapy. For male patients, recent progress in ART could lead to an improved rate of fatherhood following treatment, even in oligozoospermic patients. Radiotherapy is used in combination with chemotherapy for early stage HL, as well as for bulky metastatic lymph nodes in advanced stage HL. A dose of 2.5–5 Gy is associated with infertility in 30%–40% of women aged 15–40 years and in 90% of women older than 40 years. Radiation is toxic, both for active and dormant follicles. For men, irradiation with 1–2 Gy is associated with a consequent risk of sterility.48 A 7.5 Gy radiation to the testis induces the highest risk of sterility.47 The data regarding the stage of the disease is controversial. Some studies report no association between disease stage and fertility, but probably the risk associated with disease stage is related to the therapy used.
Second-line therapies include DHAP (dexamethasone, high-dose cytarabine, cisplatin), ICE (ifosfamide, carboplatin, etoposide), IGEV (ifosfamide, gemcitabine, etoposide, vinorelbine), GDP (gemcitabine, dexamethasone, cisplatin), GVD (gemcitabine, vinorelbine, dexamethasone), MINE (mesna, ifosfamide, novantrone, etoposide) chemotherapy regimens, none of which have yet been evaluated for the risk of infertility. The infertility risk associated with an ASCT was not prospectively evaluated so far, but few case reports of pregnancies after BEAM (BCNU, etoposide, cytarabine, melphalan) conditioning chemotherapy have been published.49,50 Several studies and reports of the European Blood and Marrow Transplantation (EBMT) have shown a high risk of infertility associated with allogeneic transplantation, especially when total body irradiation (TBI) was used as part of the conditioning regimen.49 However, up to 20%–25% of patients recover their fertility several years after myeloablative allogeneic transplantation.47
Overall, on a Dutch cohort, de Bruin et al51 have shown that 97 out of 518 patients treated with chemotherapy for HL developed a premature menopause. The largest study that evaluated the risk of infertility in patients treated for HL was published by Swerdlow et al.50 The study evaluated 2,127 female patients treated from 1960 to 2004, with the evaluation being made from 2003 to 2012. Among these patients, 1,292 developed early or premature menopause. The group showed a cumulative risk of infertility associated with age, at least six cycles of alkylating agent therapy, BEAM chemotherapy, or 5 Gy pelvic radiotherapy. There was an increased risk for older patients, but there was also evidence of cumulative incidence years after treatment.
TARGETED NEW THERAPIES AND FERTILITY
In the last 2 years, important progress has been made in the treatment of HL with monoclonal antibody-based drugs. These novel targeted molecules have shown unprecedented overall response rates for heavily pretreated patients, most of whom are in relapse after multiple lines of chemotherapy and ASCT.52,53 It is too early to have fertility studies considering the limited experience, but specialists and patients should be aware of safety information regarding pregnancies. Some information is available for rituximab, in use since 1997 for different Non-Hodgkin’s lymphoma (NHL) subtypes, and rituximab appears to be safe.54,55 There is limited data on fertility issues, but the available animal studies show embryofetal abnormalities correlated to targeted therapy. The anti PD-1 molecules are IgG4 that crossed the placental barrier, and monomethyl auristatin E (MMAE) has proven testicular toxicity.
Brentuximab vedotin is an anti-CD30 antibody drug conjugate, covalently linked to a antimicrotubule agent monomethyl auristatin E (MMAE), with proven efficacy in CD30 lymphoproliferative diseases such as HL, anaplastic large cell lymphoma (ALCL), and other types of non-Hodgkin’s lymphoma (NHL).56–59 This drug is approved for relapsed/refractory HL after ASCT or after two prior lines of chemotherapy, brentuximab vedotin showed an overall response rate of 75% and a complete response rate of 34%, in phase 2 trials as a single agent.60,61 Recent results of the AETHERA study group suggest a role of brentuximab vedotin treatment as consolidation after ASCT for high risk patients.62CD30 is not expressed in physiological conditions, with some exceptions such as decidual cells in the uterus and endometrium during pregnancy.63,64
Up to this point, no studies have been published regarding the use of brentuximab in pregnant women, but preclinical studies on animal models have shown significantly decreased embryo viability and fetal malformations.61 Thus, both HL and ALCL patients are advised not to become pregnant during brentuximab therapy and 6 months after the last dose. For men treated with brentuximab, the same rules as for chemotherapy should be applied regarding sperm collection, since non-clinical studies have revealed testicular toxicity. MMAE has aneugenic properties leading to testicular atrophy and degeneration, that are partially reversible. Male patients should use contraception methods for at least 6 months after the last dose. There is no information on breastfeeding, but it is possible that a very low quantity of brentuximab could be found in milk, since it is a large protein.