Fertility preservation in lymphoma patients treated with immunochemotherapy regimens with or without radiotherapy: results of a retrospective multicenter Italian study (Ferty care).

This is a retrospective, multicentric study, aimed to describe the real-life application of fertility preservation methods during treatment in female lymphoma patients, aged 18-40 years old, diagnosed between Oct 1st/2010 and May 31st/2018. Among 414 women included, median age was 28 years old, histologies were: HL 74%, PMBCL 13%, DLBCL 10%, others 3%. First line treatments were: ABVD in 295 (71%), R-CHOP like in 102 (25%), higher intensity regimens in 17 (4%) cases. Fertility preservation strategies were: GnRHa in 315 (78%), Oral Contraceptive in 41 (10%), oocytes and ovarian tissue cryopreservation in 55 and 42 patients, respectively. After therapy, we observed a restored regular period in 293 (70%) and premature ovarian failure (POF) in 33 (8%), Furthermore we recorded 43 pregnancies, all spontaneous with 5 years median follow-up. Median age at diagnosis and number of lines of treatment correlate with higher rate of amenorrhea, risk of POF and menopause (p < 0.001).

Effects of ABVD chemotherapy on ovarian function: epidemiology, hormonal dosages and ultrasound morphologic analyses in 270 patients with Hodgkin's disease.

Introduction: Classical Hodgkin Lymphoma (HL) is a lymphoproliferative disease typically diagnosed in the young. The excellent results obtained with current treatment lead to long survival with age-related complications affecting patients' survival and quality of life. One issue affecting HL patients is infertility. This problem can be easily overcome in males with seminal liquid cryopreservation, however, in females it is more complex either in terms of the quality of the cryopreserved material or the patients' age at diagnosis. Moreover, not all chemo- or radio-therapies have the same negative impact on fertility.The main objectives of this study was to collect epidemiological information on HL patients involved in fertility preservation counseling and to analyze the impact of ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine), the standard treatment for HL, on ovarian function, hormonal levels and ovarian and uterine tissue morphologies. Patterns of fertility preservation were also reported. Methods: Data were obtained from 270 female patients at HL onset who were interested in fertility counseling prior to therapy initiation. Each patient was assessed at HL diagnosis for levels of Anti-Mullerian Hormone (AMH), Follicle Stimulating Hormone (FSH), and 17ß-oestradiol (17ß-oe), with additional assessments at 6 and 12 months after chemotherapy. Patients were evaluated with ultrasound scans to study the number of ovarian follicles and the degree of uterine thickness at the same timepoints. Results: The average patient AMH level showed a statistically significant reduction at 6 months after chemotherapy (p=0.05) and by the 12 month time point returned to near pre-chemotherapy values. FSH and 17ß-oe levels did not significantly vary throughout the study period. ABVD chemotherapy was associated with a significant reduction of both ovarian follicles and endometrial thickness at the 6 month time point followed by a recovery at the 12 time point in both ovaries. Different results were observed when patients changed treatment to a more intensive one. Discussion: Based on the results from the hormonal measurements and the follicle echography, it appears that the toxic effect of ABVD on fertility is transient, whereas, in contrast, more intensive therapies may potentially be more harmful and long-lasting.

Chronic Myeloid Leukemia and Pregnancy: When Dreams Meet Reality. State of the Art, Management and Outcome of 41 Cases, Nilotinib Placental Transfer.

The overwhelming success of tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia (CML) patients has opened a discussion among medical practitioners and the lay public on the real possibility of pregnancy and conception in females and males with CML. In the past 10 years this subject has acquired growing interest in the scientific community and specific knowledge has been obtained "from bench to bedside". Embryological, pharmacological, and pathophysiological studies have merged with worldwide patient databases to provide a roadmap to a successful pregnancy and birth in CML patients. Male conception does not seem to be affected by TKI therapy, since this class of drugs is neither genotoxic nor mutagenic, however, caution should be used specially with newer drugs for which little or no data are available. In contrast, female patients should avoid TKI therapy specifically during the embryonic stage of organogenesis (5-12 weeks) because TKIs can be teratogenic. In the last 15 years, 41 pregnancies have been followed in our center. A total of 11 male conceptions and 30 female pregnancies are described. TKI treatment was generally terminated as soon as the pregnancy was discovered (3-5 weeks), to avoid exposure during embryonic period and to reduce the risk of needing treatment in the first trimester. Eleven pregnancies were treated with interferon, imatinib or nilotinib during gestation. Nilotinib plasma levels in cord blood and maternal blood at delivery were studied in 2 patients and reduced or absent placental crossing of nilotinib was observed. All of the patients were managed by a multidisciplinary team of physicians with obligatory hematological and obgyn consultations. This work provides an update on the state of the art and detailed description of pregnancy management and outcomes in CML patients.

Preliminary results of a counselling programme for fertility preservation in female cancer patients: The experience of the GEMME DORMIENTI network.

OBJECTIVE: To describe a population of patients referred for fertility preservation (FP), how to efficiently provide FP care, and how FP care changed over time. METHODS: This longitudinal observational study enrolled 281 female cancer patients referred between 2013 and 2016 to the non-profit organisation Gemme Dormienti ONLUS (GD) for FP care. All patients underwent the same battery of instrumental and laboratory diagnostic tests. GnRHa therapy was started at least seven days before CTh treatment. RESULTS: From 2013 to 2016, we observed a progressive increase in the number of patients referred for FP care. Out of 251 eligible patients, 135 patients were treated with GnRHa only, and 72 patients underwent GnRHa therapy and cryopreservation. The median time from GD referral to oocyte and ovarian tissue cryopreservation was 11 and 5 days respectively. Tissue cryopreservation requests increased during our study period (from four cases in 2013 to 17 cases in 2016). During follow-up, 17ß-estradiol and FSH levels were significantly increased (p < .0001), and AMH levels were significantly decreased (p < .0001). CONCLUSION: The rapid increase in the number of patients who requested FP care and in the complexity of FP procedures overtime reflects the need to improve quality of life for cancer patients.

Gonadal Function Recovery and Fertility in Women Treated with Chemo- and/or Radiotherapy for Hodgkin's and Non-Hodgkin Lymphoma.

BACKGROUND: Fertility and gonadal function represent one of the most important aspects for long-term lymphoma survivors. AIMS: The aim of our study was to determine possible risk factors, such as age at treatment, chemotherapeutic regimen, protection with oral contraceptives (OCs), and gonadotropin-releasing hormone (GnRH) analogues in female patients treated for Hodgkin's lymphoma (HL) or non-Hodgkin lymphoma (NHL) at a reproductive age. METHODS: Patients between the age of 16 and 50 years at the time of HL or NHL diagnosis were selected. Eligible patients were requested to respond to a questionnaire by phone interview about fertility, menstrual status, sexual aspects, and treatment with OCs or GnRH analogues during chemotherapy. RESULTS: The resumption of menstrual activity was associated with the use of the OCs and GnRH analogues during chemotherapy (p = 0.008 and 0.034, respectively). At univariate analysis, the use of OCs during chemotherapy was associated with a lower risk of amenorrhea (prevalence ratio [PR] = 0.37; 95% CI 0.17-0.82). A higher age at the time of treatment correlated positively with therapy-induced amenorrhea, with a difference of 12.8 years between the mean age at diagnosis of the women with therapy-induced amenorrhea and those who resumed their menses. Amenorrhea was significantly higher in women receiving R-CHOP than in women treated with ABVD (PR = 6.00; 95% CI 2.32-15.54). Moreover, NHL had an infertility PR of 1.51 (95% CI 0.86-2.45) at multivariate analysis compared to HL. CONCLUSIONS: This study suggests a possible role of pharmacological prophylaxis with OCs and GnRH analogues.

Possible involvement of hMLH1, p16(INK4a) and PTEN in the malignant transformation of endometriosis.

Endometriosis is a common gynecologic disease, which generally follows a benign course. Notwithstanding, several clinical and histologic studies as well as molecular data show that endometriosis could be a precursor of sporadic endometrioid and clear cell carcinomas at extrauterine loci. Several reports have implicated alterations of the hMLH1 and p16(ink4a) (p16) genes, in particular hypermethylation of the promoter region, and of the PTEN gene, principally genetic mutations, in endometrial and ovarian cancers and have indicated that these alterations are already present in precancer conditions. In this report, we analyzed the methylation status of hMLH1 and p16 and the protein expression of PTEN and hMLH1 in 46 cases of endometriosis stages III and IV to better define the possible involvement of these genes in the malignant transformation of endometriosis. We found abnormal methylation of hMLH1 in 4 of the 46 cases (8.6%). In addition, these cases had no detectable hMLH1 protein expression. Regarding patients with hMLH1 alterations, 2 were classified as stage IV and 2 showed coexistent endometriosis and carcinoma. Only 1 case of endometriosis (2.17%), classified as atypical, showed abnormal methylation of p16. Reduced PTEN protein expression was detected in 7 of 46 cases (15.21%): 5 were clinically classified as stage IV, and the other 2 presented both cancer and hypermethylated hMLH1. Our preliminary study suggests that reduced expression of both hMLH1 and PTEN may be involved in the malignant evolution of endometriosis and should be used as markers of neoplastic transformation in aggressive endometriosis with elevated tumor markers.