Infertility After Treatment for Hematological Malignancy

Fertility is defined as the inherent ability to conceive a child, while infertility is clinically characterized as the failure to achieve pregnancy after 12 months or longer of consistent, unprotected sexual activity. Hematological Malignancies (HMs) refer to cancers that impact the blood, bone marrow and lymphatic system, including leukemia, lymphoma, and multiple myeloma [1]. These types of cancer are frequently identified in children, adolescents, and young adults, who possess considerable reproductive potential. These malignancies are often diagnosed in children, adolescents, and young adults-populations with significant reproductive potential [2].

Treatment modalities for HMs typically include chemotherapy, radiotherapy, hematopoietic stem cell transplantation (HSCT), and in some cases, immunotherapy and targeted biological agents [3]. While these treatments have significantly improved survival rates, they are also associated with adverse effects, including gonadal toxicity, which can lead to temporary or permanent infertility [4]. The gonadotoxic effects of cancer treatments like chemotherapy and radiation refer to the damage these therapies can cause to the reproductive organs, specifically the ovaries in females and the testes in males, leading to impaired fertility or even permanent infertility [5]. This review explores the impact of HM treatments on fertility, available fertility preservation strategies, and recommendations for clinical practice..

Chemotherapy

Chemotherapy, especially alkylating agents like cyclophosphamide and busulfan, is known to be highly gonadotoxic. These agents destroy rapidly dividing cells, including germ cells in the ovaries and testes, leading to reduced ovarian reserve or azoospermia [6]. In females, they can damage ovarian follicles, leading to decreased ovarian reserve or premature ovarian failure. In males, they can impair spermatogenesis and damage the DNA in sperm cells [5]. The degree of damage is influenced by the patient’s age, gender, the specific drug type and dosage, as well as the total exposure over time, and whether multiple gonadotoxic agents are used together [5,7].

Radiotherapy

Total body irradiation (TBI), commonly used before HSCT, can severely damage gonadal tissue. In females, radiation can deplete ovarian follicles; in males, it impairs spermatogenesis and may cause Leydig cell dysfunction [8]. Even low-dose radiation to the pelvis or brain (impacting the hypothalamic-pituitary gonadal axis) can disrupt reproductive function. When targeted near or involving the pelvic area or brain (especially the hypothalamus or pituitary gland), radiation can severely impact reproductive organs. Also, in females, it can destroy ovarian tissue and alter the uterus’s ability to support pregnancy. In males, it can damage the testes and reduce testosterone levels, impairing sperm production and sexual function [5,8].

Hematopoietic stem cell transplantation (HSCT)

HSCT involves intensive conditioning regimens that combine high-dose chemotherapy and/or radiation, increasing the risk of infertility. Stem cell transplantation has potential long-term impact on gonadal function [5]. Studies show that up to 90% of patients undergoing HSCT develop long-term gonadal failure, particularly in allogeneic transplant settings [9]. HSCT negatively influences sexual health and quality of life in both male and female recipients [10], thus impairing even the ability to get pregnant.

Targeted therapy and immunotherapy

Novel agents, including tyrosine kinase inhibitors and monoclonal antibodies, are generally less gonadotoxic than “traditional” treatments [11]. They have the ability to modify immune responses and may lead to enduring side effects, with increasing apprehensions regarding gonadotoxic effects and their potential influence on both male and female fertility. Immunotherapies (immune checkpoint inhibitors, immunomodulators, monoclonal antibodies), and CAR-T therapies, can result in increased levels of proinflammatory cytokines and immune-related adverse events, potentially worsening fertility issues. The inflammation associated with immunotherapy, marked by cytokine imbalances and the activation of specific pathways (e.g. AMPK/mTOR), has been linked to the mechanisms that impair fertility [12]. There is a scarcity of clinical data regarding the impact of CAR-T cell therapy, on fertility [13]. Overall, information regarding long-term fertility outcomes for this agent remains scarce, necessitating a cautious approach [11,12].

Currently, there is no established procedure for maintaining fertility in these individuals [13]. Recent advancements in assisted reproductive technologies have made it feasible to mitigate the infertility effects associated with oncological therapies; however, the aspect of fertility preservation has been relatively overlooked for women with hematological disorders receiving gonadotoxic treatments [14].

For females, the most established fertility preservation methods include the cryopreservation of embryos, mature oocytes and ovarian tissue, and oocyte in vitro maturation, which require hormonal stimulation and transvaginal egg retrieval prior to initiating cancer treatment [14]. This option is best suited for post-pubertal patients who can delay therapy for a short time. Ovarian tissue cryopreservation is increasingly used, especially in prepubertal girls or those who need urgent treatment. It involves the surgical removal and freezing of ovarian cortical tissue, which can later be reimplanted to restore fertility and hormonal function. Additionally, the use of Gonadotropin-Releasing Hormone (GnRH) agonists during chemotherapy has been explored as a method to protect ovarian function. While some studies show reduced ovarian damage, the results are mixed, and this method is considered adjunctive rather than definitive [14-16].

For males, the standard fertility preservation approach is sperm cryopreservation, which should ideally be done before the initiation of treatment. It is simple, non-invasive and widely accessible. For prepubertal boys, who are unable to produce mature sperm, testicular tissue cryopreservation is currently experimental but holds promise for future fertility restoration. In cases where patients are azoospermic after treatment, Testicular Sperm Extraction (TESE) may be an option if spermatogenesis is still occurring in isolated regions of the testes. In all cases, early identification and timely referral to reproductive specialists are crucial for effective fertility preservation [16-18].

Nonetheless, maintaining fertility in prepubescent patients presents significant challenges. Consequently, hematologists are required to inform patients about the possible gonadal toxicity associated with cancer therapies and to provide the most suitable options for fertility preservation [13].

One of the most critical recommendations is the integration of fertility counseling into the initial treatment planning for patients with hematological malignancies. Oncologists should discuss the potential gonadotoxic effects of therapy and present available fertility preservation options as early as possible. Patients and families should receive clear, age-appropriate information that supports informed decision-making. Special consideration should be given to pediatric and adolescent patients, where parents or guardians must also be involved in discussions about future fertility [5,19,20].

Additionally, a multidisciplinary team approach should be adopted, involving oncologists, reproductive endocrinologists, psychologists and fertility specialists. Establishing institutional protocols and referral pathways can streamline the process and ensure timely intervention. Continued research is also necessary to improve existing preservation methods, understand the longterm reproductive outcomes of newer treatments and develop guidelines that reflect evolving clinical evidence. Emphasizing fertility preservation as part of comprehensive cancer care not only supports survivorship but also improves overall quality of life [19- 21].

Incorporating fertility preservation into the standard care pathway for patients with HMs is crucial and essential to safeguarding long-term quality of life and reproductive autonomy. Oncology healthcare providers have a critical responsibility to initiate early, proactive discussions about potential gonadotoxic risks and fertility options, particularly in pediatric, adolescent, and young adult populations. Institutional protocols should be standardized to guarantee timely, multidisciplinary counseling and streamlined referrals to fertility preservation services before treatment initiation. Furthermore, ongoing clinical research and longitudinal cohort studies are imperative to assess the reproductive outcomes and gonadal toxicity profiles of emerging cancer therapies, including targeted agents and immunotherapies. A comprehensive, evidence-based approach to onco-fertility care is vital to addressing the complex needs of this vulnerable patient group.

Survivors of hematological malignancies face a significant risk of infertility due to the gonadotoxic nature of cancer therapies. While survival rates have improved, fertility preservation remains a critical aspect of comprehensive cancer care. Early intervention, patient education, and a multidisciplinary approach are fundamental to safeguarding reproductive potential in this vulnerable population.

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