Brentuximb is an important acquisition for the HL treatment, but, regarding conception, the same rules as for chemotherapy should be applied.
Nivolumab is a fully human anti PD-1-monoclonal antibody, used in clinical trials for the treatment of HL in the setting of relapsed/refractory disease after ASCT followed by brentuximab vedotin therapy.65In a recent large Phase II clinical trial, 80 patients who failed both ASCT and brentuximab vedotin have received nivolumab. The overall response rate was 66%, with a complete response of 8.8% and partial response of 57.5% of patients. The 6-month overall survival was 99%.66–68 So far, there are no studies on fertility in men or women treated with nivolumab. There is no data on pregnancy outcome under nivolumab treatment, but animal studies show embryofetal toxicity.69 The only published literature is from various regulatory agencies recommendations for contraception during nivolumab therapy and 5 months after the last dose.
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Pembrolizumab is another anti PD-1 monoclonal antibody tested in patients with HL.70 Recently, the results from the Keynote-013 Phase I/II clinical trial have been reported with impressive outcome.71Among the 31 patients treated with pembrolizumab, all of them after relapse from ASCT, the overall response rate was 65%, with 16% complete response and 48% partial response rates.72 Still, there is no available clinical data on fertility under pembrolizumab therapy, but animal studies have revealed no negative effects. As with nivolumab, there are no data on the use of pembrolizumab in pregnant women, but animal studies reveal fetal harm and fetal loss. So far, recommendations treatment with pembrolizumab is not to be used in pregnancies.
Still, both anti PD-1 antibodies are IgG4, known to cross the placental barrier.73,74 PD-1 blockade with nivolumab or pembrolizumab is safe and effective. Treatment is usually administered for 3–6 months, up to 2 years. Retreatment is also allowed in the case of initial response, with most frequent adverse events being the immune reactions. It is important to emphasize that patients treated with anti PD-1 monoclonal antibodies are heavily pretreated with chemotherapy and ASCT, both therapies known to impair fertility in men and women. Current studies evaluate the role of anti PD-1 monoclonal antibodies as first-line therapy. We hope for new data on fertility complications due to these targeted molecules.
Rituximab is a chimeric mouse/human IgG1k monoclonal antibody targeting the B cell surface antigen CD20.75–77 Rituximab is used in the clinic for treating diffuse large B cell NHL, follicular NHL, as well as for nodular lymphocyte predominant HL. The median half-life is 18–22 days, but the drug can be detected in blood up to 24 weeks after administration. The B cell depletion induced by rituximab can last for 6 months to years in some patients. Chakravarty et al78 have shown that most of the 231 pregnancies included in the study, with preconceptional and antepartum exposure to rituximab, resulted in uncomplicated live births. In this study, there was no pattern of congenital abnormalities identified and associated with rituximab. There was also no pattern of neonatal infections, but cytopenias were detected in seven of the eleven reports. This observation has led to the recommendation of blood count for all newborns exposed to rituximab, especially shortly before or during gestation. Given the prolonged B-cell depletion after rituximab administration, regular check-ups for both the mother and the newborn should be performed. No clear conclusion can be drawn from current reports regarding male exposure to rituximab, and data are still insufficient for the evaluation of gonadal toxicity in men.78
GONADAL FUNCTION EVALUATION AND FERTILITY PRESERVATION OPTIONS
There is no consensus on ideal parameters of fertility.79 FSH is elevated in the case of impaired ovarian function, and it has been used as the most important ovarian function parameter, but it’s high intercycle variability makes this serum analysis unreliable. Currently, AMH is being used as the best tool for assessment of ovarian function, as it demonstrated high sensitivity and stability.80 Another evaluation assay is the determination of inhibin B hormone, secreted by the follicles recruited during the ovarian cycle and involved in the negative regulation of FSH. Nevertheless, this type of analysis is not available in all laboratories, especially in developing economies.81 The transvaginal ultrasound performed at day 3 of the menstrual cycle provides the number of follicles between 2 and 10 cm, that correlate with the ovarian reserve.82 Unfortunately, in the case of amenorrhea, the ultrasound has not proven to be useful. Most specialized centers in reproductive techniques use both AMH and/or FSH serum levels and ovarian ultrasound.83,84
For male patients, the best available assessment is semen analysis, which provides data on sperm count, as well as vitality and mobility of the spermatozoids. The test should be performed at least 3 months after chemotherapy, as spermatogenesis takes ~74 days. FSH and inhibin B serum levels could also be used.
The most important step on fertility preservation for patients treated for HL is the multidisciplinary collaboration between hematologist, ART specialist, and gynecologist. The use of gonadotropin-releasing hormone analogs (GnRH-a) during chemotherapy is still controversial.85,86 Several randomized trials suggest the efficacy of GnRH-a in the reduction of chDOR risk for female patients undergoing chemotherapy, based on a chemical-induced menopause which can protect the ovary from the cytotoxic effect. A German trial has evaluated the use of oral contraceptives in comparison to GnRH-a for female patients treated with escalated BEACOPP, and found no efficacy of GnRH-a. Currently, there is no evidence that GnRH-a administration during chemotherapy could increase the rate of pregnancies, with no clear recommendation regarding their use. Still, important advantages for the clinician are the good control of the menstrual cycles and the reduction of irregular bleeding.87–91
Currently, three preservation methods are available for female patients: oocyte cryopreservation, in vitro fertilization for embryo cryopreservation, and cryopreservation of ovarian tissue. Recently, a new technique of retrieval of cumulus oocyte complexes, followed by in vitro maturation and vitrification, in combination with ovarian tissue cryopreservation, was reported in France.92,93 With regard to oocyte cryopreservation, ovarian stimulation for 4–6 weeks is still needed, and the success rate is only 3%.94,95 Fertilization of the oocyte by intra-cytoplasmic sperm injection and subsequent vitrification could increase the success rate to 6.8%.96 The in vitro fertilization followed by embryo cryopreservation is a feasible option for patients with a stable partner, where a delay in chemotherapy is not contraindicated, and where an ovarian stimulation of 9–14 days, but sometimes 4–6 weeks, is possible. The success rate has been reported to be 18%.20
The cryopreservation of the ovarian tissue is a new promising procedure, but it’s results need further confirmation, since only a few pregnancies have been reported so far, with a risk of 50% loss of ovarian reserve and an additional risk of malignant cell reimplantation.97
For male patients that undergo chemotherapy, semen collection and preservation must be proposed to the patient prior to therapy. There is a known risk of subfertility in HL patients,19,20 and normal sperm is essential for embryo development.98,99 It is of utmost importance to perform quality control assays prior to preservation. There is no consensus on the ideal method of quality measurement and there are several available methods such as the SCSA (sperm chromatin structure assay;100 the detection of single and double DNA breaks by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)101 the comet assay,102 or flow cytometry using monobromobimane for reactive SH groups in protamines and using chromomycin A3 for DNA compaction.103 O’Flaherty et al19 have reported increased DNA damage in newly diagnosed HL patients when compared with controls, using two control methods: comet assay and flow cytometry with monobromobimane and chromomycin. Semen collection may be possible after initiation of chemotherapy, but the risk of genetic defects in the offspring is unknown.19 Some groups report success with cryopreservation and subsequent transplantation of spermatogonial stem cells, but these options are still experimental and are offered only to patients in whom semen cryopreservation is not possible.104 As in female patients, there is limited data regarding the efficacy of hormone suppression in reducing the risk of infertility during chemotherapy.105,106 All patients should be offered the possibility of sperm preservation, with the best local available quality control assay.
The American Society of Clinical Oncology published in 2013 updated recommendations on fertility issues in patients with cancer. For men, sperm cryopreservation is the recommended method as the only proven fertility preservation method. For women, embryo and oocyte cryopreservation are established fertility preservation methods. The authors suggest ovarian transposition in the case of pelvic radiotherapy. Nor for men or women, there is no recommendation for hormonal suppression, since there is insufficient data on effectiveness.107
Figures 1 and 2 present the algorithms for fertility preservation in HL patients, as a proof-of-concept.
