Background
Preventing premature ovarian failure (POF) is a major challenge in oncology. With conventional regimens, cytotoxicity‐associated POF involves primordial follicles (PF) pool depletion by ...apoptosis or overactivation mechanisms, notably mediated by the ABL/TAp63 and PI3K/Akt/mTOR pathways. New anticancer treatments have been designed to target pathways implicated in tumor growth. Although concerns regarding fertility arise with these targeted therapies, we hypothesized that targeted therapies may exert off‐tumor effects on PF that might delay POF. We provide an overview of evidence concerning these off‐tumor effects on PF. Limitations and future potential implications of these findings are discussed.
Design
PubMed was searched by combining Boolean operators with the following keywords: fertility, ovarian, follicle, anti‐tumoral, cancer, targeted, cytotoxic, and chemotherapy.
Results
Cisplatin‐related PF apoptosis via the ABL/TAp63 pathway was targeted with a tyrosine kinase inhibitor, imatinib, in mice, but effects were recently challenged by findings on human ovarian xenografts in mice. In cyclophosphamide‐treated mice, PI3K/Akt/mTOR pathway inhibition with mTOR inhibitors and AS101 preserved the PF pool. Proteasome and GSK3 inhibitors were evaluated for direct and indirect follicle DNA damage prevention. Surprisingly, evidence for cytotoxic drug association with PF pool preservation was found. We also describe selected non‐anticancer molecules that may minimize gonadotoxicity.
Conclusion
Not all anticancer treatments are associated with POF, particularly since the advent of targeted therapies. The feasibility of associating a protective drug targeting PF exhaustion mechanisms with cytotoxic treatments should be evaluated, as a way of decreasing the need for conventional fertility preservation techniques. Further evaluations are required for transfer into clinical practice.
Implications for Practice
Anticancer therapies are associated with infertility in 10%–70% of patients, which is the result of primordial follicles pool depletion. Alone or associated with gonadotoxic treatments, some targeted therapies may exert favorable off‐targets effects on the primordial follicle pool by slowing down their exhaustion. Current evidence of these effects relies on murine models or human in vitro models. Evaluation of these protective strategies in humans is challenging; however, if these results are confirmed with clinical and biological data, it not only could be a new approach to female fertility preservation but also would change standard fertility strategies.
Fertility preservation during cancer treatment is challenging. This review focuses on studies reporting potential favorable off‐targets effects of anticancer treatments that may prevent ovarian failure.
Tisagenlecleucel therapy has shown promising efficacy for relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, relapses occur in 30-50% of patients. ...Determinants for CD19
versus CD19
relapses are poorly characterized. We report on 51 patients with R/R BCP-ALL (median age 17 years) infused with tisagenlecleucel after lymphodepletion. Complete remission rate at D28 was 96%. Prior blinatumomab increased the risk of early failure at D28. The 18-month cumulative incidence of relapse (CIR), event-free survival (EFS), and overall survival (OS) were 51%, 44%, and 74%, respectively, at a median follow-up of 15.5 months. Factors associated with a high tumor burden (occurrence of cytokine release syndrome) and prior blinatumomab were associated with an increased CIR, and a shorter EFS and OS. Pre-lymphodepletion high disease burden (MRD ≥ 10
, SHR 10.4, p = 0.03) and detectable MRD at D28 (SHR 7.2, p = 0.006) correlated with an increased risk of CD19
relapse. Low disease burden (SHR 5.3, p = 0.03) and loss of B-cell aplasia (BCA) (SHR 21.7, p = 0.004) predicted an increased risk of CD19
relapses. These data highlight the impact of prior therapy on patient outcome. Finally, detectable MRD at D28 and loss of BCA both define patients at high risk of relapse for whom additional interventions are needed.
Introduction
Infertility is a major late effect after allogeneic hematopoietic stem cell transplantation (HSCT). Post-transplant complications such as graft versus host disease (GVHD) may also impact ...health-related quality of life. The aim of this study was to evaluate sequalae of disease and transplant on fertility, pregnancy wish, affective and sexual life in female recipients.
Patients and methods
This unicentric prospective study was conducted from 2014 to 2016 in Saint Louis Hospital (Paris, France). To be included, women had to be a) aged > 18 years with a minimal follow-up of 2 years after an allogeneic HSCT b) younger than 35 at HSCT c) in persistent complete remission of their hematological disease. In the first part of the study, data related to affective, sexual life and pregnancies were collected by self-reported surveys. Responses to open-ended questions were analyzed using a thematic analysis approach. The second part, restricted to patients younger than 40 years at inclusion, evaluated post-transplant ovarian function by hormonal dosages. The study was approved by an institutional review board.
Premature ovarian failure (POF) was defined by amenorrhea and follicle stimulating hormone >25 IU/L.
Sixty-three patients were included at a median age of 31.3 years IQR, 24.9-37.3: 58 completed the survey and 34 were evaluated for ovarian function. Only 8 patients had already had children before HSCT. Median age at HSCT was 23.4 years IQR, 18.3-28. Twenty-nine (46%) patients were transplanted for acute leukemia and 16 (25%) for aplastic anemia. Conditioning regimen was myeloablative (MAC) in 39 patients (62%), reduced (RIC) in 22 (35%) and sequential in 2 (3%). Seventeen patients (27%) benefited from a fertility preservation procedure (82% performed after 2004): ovarian tissue cryopreservation alone (n=7) or associated with oocyte cryopreservation (n=9) (missing data n=1). Thirty-two (51%) patients experienced chronic GVHD and 16 (44% of assessed patients) gynecologic GVHD.
Results
Fifty patients (86%) reported hypoestrogenism symptoms, mainly vaginal dryness (n=44, 76%) and hot flushes (n=32, 55%). Forty-four patients (76%) reported negative impact of transplant on their sexual life: 18 (31%) a decrease in libido, 17 (29%) experienced dyspareunia, 14 (24%) highlighted a relationship between physical sequelae and sexuality, and 19 (33%) reported a loss of self-confidence. Twenty-seven patients (47%) indicated that disease and treatments had decreased their desire for pregnancy, mainly for fear of relapse, disease transmission, and also due to negative self-representation.
Most patients (n=56, 97%) were treated with hormone replacement therapy (HRT). Thirty-six patients (64%) temporarily interrupted their HRT. During this break, 14 (39%) experienced return of menses. POF was diagnosed in 25 of the 34 (74%) patients evaluated: 19/20 (95%) after MAC, 6/12 (50%) after RIC and none after sequential.
Twenty-two patients (38%) expressed a desire for pregnancy after transplant; among them, 9 (41%) had a child. In the whole population, 13 patients (21%) got pregnant: 8 naturally (1 after MAC and 7 after RIC or sequential regimen) and 5 through assisted reproductive technology. Natural pregnancy occurred in 2.6% (1/39) of patients after MAC, 22.7% (5/22) after RIC and 100% (2/2) after sequential conditioning regimen. Four of these 8 patients were transplanted for aplastic anemia, 2 for acute leukemia, 1 for sickle cell disease and 1 for lymphoma. Among patients who benefited from assisted reproductive technology, 4 resorted to oocytes donation and one had classical in vitro fertilization. Finally, 3 women adopted children.
A univariate logistic regression analysis was performed to evaluate the impact of age at transplant and at inclusion, conditioning regimen, disease and chronic GVHD on post-transplant outcomes. Table 1 shows variables significantly associated with POF, return of menses, pregnancy desire and natural pregnancies.
Conclusion
This study highlights the major physical and psychological impact of disease and transplant on affective, sexual, and reproductive outcomes in women. In this series, RIC and sequential regimens allowed for post-transplant ovarian function preservation in more than 50% of patients. Improvement of post-transplant fertility and management of treatment impact on sexual and affective life has to be a priority in long-term survivors of HSCT.
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Peffault de Latour:Amgen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Robin:Novartis Neovii: Research Funding. Michonneau:Neovii: Consultancy. Boissel:NOVARTIS: Consultancy.
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