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. 2025 Jul 25;104(8):4071–4080. doi: 10.1007/s00277-025-06426-7

Semen quality in acute leukemia patients: a retrospective study

Alessandra Buonacquisto 1,4,#, Maria Ilaria Del Principe 2,3,6,✉,#, Francesco Pallotti 4, Serena Bianchini 1, Elisa Buzzatti 2, Luisa Caponecchia 1, Sabina Chiaretti 5, Gaia Cicolani 1, Anna Chiara Conflitti 1, Silvia Di Chiano 1, Ludovica Fucci 5, Deborah Kasmi 5, Clara Minotti 5, Giovangiacinto Paterno 2,3, Ilaria Tiravanti 2, Adriano Venditti 2,3, Francesco Lombardo 1, Donatella Paoli 1
PMCID: PMC12431908  PMID: 40707629

Abstract

Among the cancer types that commonly affect men of reproductive age there are leukemias. In literature, little is known about the correlation between semen quality and acute leukemia. It could be assumed that the disease may evoke a systemic response mediated by cytokines secreted by tumor cells, which may have an impact on semen parameters. Significant advances in survival rates due to new therapeutic strategies have focused attention on fatherhood and fertility preservation. The aim of this study was to evaluate semen quality of patients with acute leukemia before chemotherapy. We also evaluated semen parameters after therapy in a subgroup of patients and we collected fertility information. Finally, we collected information about the feasibility of the semen cryopreservation and evaluated any shifts in the approach to fertility preservation in these patients. A retrospective study was conducted, and it included the collection of data related to: semen analysis, information related to paternity desire and childbearing, number of cryopreservations performed over the years and the feasibility of the procedure. The median semen characteristics of these patients were above the 25° percentile, before cancer treatment. After therapies, an increase of the percentage of azoospermic at one year of follow-up can be observed. Four patients succeeded in achieving fatherhood through at least one cycle of assisted reproductive technology. These results allow us to recommend increased awareness among onco-hematologists about cryopreservation of semen for acute leukemia patients to ensure that they can become parents in the future and face the treatment course with greater confidence.

Keywords: Sperm, Acute leukemia, Cryopreservation, Fatherhood, Oncohematology, Oncofertility

Introduction

Cancers can impact both current and future male fertility due to the disease itself and any gonadotoxic treatments [1]. Recent advances in therapeutic strategies have greatly improved life expectancy, especially for young patients, resulting in a focus on fertility preservation. Cancer types that commonly affect men of reproductive age are testicular cancer (TC), Hodgkin’s and non-Hodgkin’s lymphomas (HL and NHL, respectively) and leukemias [2]. While the effects of TC, HL, and NHL on semen parameters, even before anti-cancer treatments, are well known, little is known about the correlation between semen quality and acute leukemia (AL) [3–7]. It has been suggested that the effect of AL on male fertility is more powerful than chronic leukemia due to the former’s more aggressive behavior [8]. Indeed, the disease may evoke a systemic response of the body mediated by cytokines and other factors secreted by tumor cells and immune system cells which could impact semen parameters [9]. However, recent improvements in survival rates for these patients due to new treatment strategies focuses attention on fatherhood and consequently fertility preservation [10–12]. In light of these remarkable advances, the lack of data on the reproductive health of patients with AL represents an important limitation in order to offer adequate oncofertility counseling to these patients. Therefore, the aims of this study were to evaluate semen quality of patients with AL before chemotherapy (at the time of semen cryopreservation) and identify any differences in semen parameters in relation to the type of leukemia, acute lymphoblastic (ALL) or acute myeloid (AML). In addition, we evaluated semen parameters after therapy in a subgroup of patients. In part of this subgroup, we also collected fertility information. These data could be very relevant to provide appropriate oncofertility counseling and raise awareness among hematologists to guide patients to semen cryopreservation before starting therapies. Due to the need for quickly initiating life-saving treatments for AL patients, preserving fertility poses a greater challenge compared to solid tumors and some lymphomas. We also aimed to obtain information about the feasibility of the semen cryopreservation. Lastly, we sought to evaluate any shifts in the approach to fertility preservation in AL patients, as observed over time in patients with other hematologic and non-hematologic malignancies.

Materials and methods

Patients

The study was approved by the Policlinico Umberto I Ethics Committee in accordance with the Declaration of Helsinki, and written informed consent was obtained from all participants. We retrospectively selected a total of 56 AL patients who attended the Laboratory of Seminology – Sperm Bank “Loredana Gandini” - Department of Experimental Medicine, “Sapienza” University of Rome between 1996 and 2023 for semen cryopreservation before starting treatment. The exclusion criteria were any comorbidity and other factors known to affect sperm parameters (history of cancer/previous cancer treatments, Klinefelter syndrome or other chromosomal/genetic abnormalities). All patients underwent a thorough medical history and physical examination at the baseline. Hematological parameters and relevant data on patients’ medical conditions were collected from available subject’s medical records. The following characteristics were recorded: date of diagnosis of AL, age, presence of comorbidities, family history of malignancy, AL genetic/cytogenetic profile, white blood cells (WBC), hemoglobin concentration (Hb) and platelet count (PLTc) at diagnosis and at the time of semen cryopreservation. Information on steroid therapy before cryopreservation, chemotherapy regimens, immunotherapy, date of allogeneic stem cell transplant, condition treatment, date of death or last follow-up were also collected.

We analyzed the pre-therapy semen parameters of these patients, as they had been entered in a computerized data management system and were thus readily analyzable. To assess the feasibility of the semen cryopreservation, we collected information on all newly diagnosed males affected with ALL or AML, younger than 50 years of age and admitted in the Department of Hematology, Policlinico Tor Vergata of Rome, between 2009 and 2023. We also investigated whether in vitro fertilization treatment was performed and whether any healthy children were born.

Semen analysis

Semen samples were collected the day of cryopreservation by masturbation directly into a sterile plastic container after 2–7 days of sexual abstinence and examined by optical microscope according to World Health Organization (WHO) criteria [13–16]. The following variables were assessed: sperm concentration (n × 106/ml), total sperm number (n × 106/ejaculate), progressive motility (%) and morphology (% abnormal forms). In cases of azoospermia (no sperm in the ejaculate), the analysis was performed twice, and the diagnosis was made only after carefully checking the entire post-centrifuge pellet.

Statistical analysis

Continuous variables are presented as mean ± SD or median and 25th-75th percentile, depending on data distribution, evaluated using the Kolmogorov–Smirnov test. Categorical variables are presented as counts and/or percentages, and comparisons were made using the chi-squared test or Fisher’s exact test, as appropriate. Spearman’s Rank Correlation test was used to investigate correlations among the available variables. A two-tailed p-value of 0.05 was considered significant. All computations were carried out using the Statistical Package for the Social Sciences (SPSS) 27.0 (SPSS Inc., Chicago, IL, USA).

Results

We retrospectively selected a total of 56 AL patients who attended the Laboratory of Seminology – Sperm Bank “Loredana Gandini” - Department of Experimental Medicine, “Sapienza” University of Rome between 1996 and 2023 for semen cryopreservation before starting treatment. The median age was 27.0 years for ALL patients and 27.5 for AML patients. A total of 22 patients (39%) underwent the allogeneic stem cell transplant procedure. To date, 10 ALL (28%) patients and 5 AML (25%) patients have died. A schematic overview of the available data is shown in Fig. 1.

Fig. 1.

Fig. 1

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Schematic overview of patient’s data we have available. ALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia

Semen quality before cancer treatment

The semen parameters of 36 ALL patients and 20 AML patients who cryopreserved their semen sample at the Laboratory of Seminology – Sperm Bank “Loredana Gandini” were evaluated prior to treatment. Sixteen patients were referred to the Laboratory of Seminology – Sperm Bank “Loredana Gandini”from the Department of Hematology, Policlinico Tor Vergata of Rome, while the remaining from Department of Hematology, Policlinico Umberto I of Rome. We considered the latest WHO criteria in use for defining sample quality [16]. The median semen characteristics of ALL patients were around the 25° percentile, while those of AML patients were around the 50° percentile. We observed no statistically significant differences in semen parameters between ALL and AML patients (Table 1).

Table 1.

Semen characteristics before cancer treatment of ALL and AML subjects

ALL, N = 361 AML, N = 201 p-value
Age (years) 28.3 ± 8.1 (27) 29.2 ± 6.7 (27.5) 0.0812
Abstinence (days) 9.1 ± 9.7 (5) 10.8 ± 9.6 (7) 0.0892
Volume (ml) 2.4 ± 1.4 (2.2) 3.0 ± 1.5 (3.1) 0.1112
Total Sperm Number (x106/ejac.) 226 ± 246.3 (150.6) 321.0 ± 268.3 (282) 0.1312
Progressive Motility (%) 38.2 ± 17.1 (42.5) 42.5 ± 14.8 (45.0) 0.3742
Abnormal Forms (%) 85.6 ± 10.3 (88.0) 80.6 ± 11.7 (83.5) 0.4362
Leukocytes (x106/ml) 1.1 ± 0.6 (0.9) 1.2 ± 0.8 (1.0) 0.5282
Germ cells 0.9893
Absent 2.0 (5.5%) 1.0 (5.0%)
Present 34.0 (94.5%) 19.0 (95.0%)
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1Mean ± SD (Median)

2Wilcoxon rank sum test

3Fisher’s exact test

ALL; acute lymphoblastic leukemia, AML; acute myeloid leukemia

Semen quality after cancer treatment

Follow-up of semen analysis was available for 10 ALL patients and 9 AML patients from T1 (1 year after the end of therapies) to T> 5 (> 5 years after the end of therapies, with a median of 9 years). A schematic overview of follow-up of semen analysis at different time points is shown in Fig. 2 for ALL and Fig. 3 for AML. Table 2 describes semen parameters at various time points (from baseline to > 5 years from the end of treatment). Despite limitations from incomplete follow up data for the whole caseload a trend of reduction from baseline for sperm progressive motility can be observed. Additionally, mean total sperm count and the percentage of abnormal forms appear to worsen compared to baseline; however, the limited sample size prevents robust analyses. These analyses, however, include semen parameters from non-azoospermic subjects. Figure 4 shows the prevalence of azoospermia at the considered time points. It can be observed that at one year, the percentage of azoospermic subjects increases dramatically with a subsequent reduction in the following years (χ2 p = 0.001). Again, however, it should be noted that the reduced sample size at each time point does not allow to associate azoospermia with specific features of the subjects (treatments, stage of the disease, age, etc.) nor to generalize this data to the leukemic population.

Fig. 2.

Fig. 2

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Schematic overview of follow-up of semen analysis in different time points for 10 ALL patients. ALL patients were named with letters from A to L. T1, T2, T3, T4, T5: respectively 1,2,3,4,5 years after the end of therapies, T> 5: >5 years after the end of therapies, the median of years > 5 was 9 years. ALL: acute lymphoblastic leukemia

Fig. 3.

Fig. 3

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Schematic overview of follow-up of semen analysis in different time points for 9 AML patients. AML patients were named with letters from M to U. T1, T2, T3, T4, T5: respectively 1,2,3,4,5 years after the end of therapies, T> 5: >5 years after the end of therapies, the median of years > 5 was 9 years. AML: acute myeloid leukemia

Table 2.

Semen parameters at various time points (from baseline to > 5 years from the end of treatment) of the patients who we have available follow-up data

T0 T1 T2 T3 T4 T5 T > 5 p-value2
Total Sperm Number (x106/ejac.) 309 ± 350.3 (150) 300.0 ± NA (300.0) 125.9 ± 196.1 (24) 64.2 ± 93.3 (18) 113.2 ± 96.3 (112) 47 ± 26.9 (47) 15 ± 18.2 (14) 0.364
Progressive Motility (%) 39.2 ± 12.4 (40) 55.0 ± NA (55.0) 26.7 ± 25.2 (30) 30 ± 22.9 (25) 41.7 ± 18.9 (50) 30 ± NA (30) 14.2 ± 16.1 (15) 0.056
Abnormal forms (%) 86.2 ± 8.4 (88) 87.0 ± NA (87.0) 94 ± 5.6 (93) 82.0 ± 6.6 (83) 87.3 ± 5 (88) 90.5 ± 3.5 (90.5) 96.0 ± 4.4 (97) 0.116
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1 Mean ± SD (Median)

2Kruskal-Wallis rank sum test; Fisher’s exact test

Fig. 4.

Fig. 4

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Prevalence of azoospermia at the considered time points. T1, T2, T3, T4, T5: respectively 1,2,3,4,5 years after the end of therapies, T> 5: >5 years after the end of therapies, the median of years > 5 was 9 years

Fatherhood information

For 16 patients (8 ALL and 8 AML) with available follow-up semen analysis at different time points, we also gathered data on their desire of paternity and fatherhood. One patient had already one child prior to its cancer diagnosis (6%), 6 patients had no children but but did not express desire for fatherhood (38%) and 9 patients expressed a desire for fatherhood (56%). Among these 9 patients, 5 attempted to achieve fatherhood through at least one cycle of Assisted Reproductive Technology (ART). Four of them succeeded in achieving fatherhood. Among these 4 patients, 2 of them used their cryopreserved sample for an ART cycle while 2 patients used fresh semen samples. None of these patients achieved fatherhood through natural fertility. The mean age of the patients who achieved fatherhood was 40 ± 7.8 years (Fig. 5).

Fig. 5.

Fig. 5

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Flowchart of the fertility data of patients with ALL and AML. ALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia; ART: artificial reproductive technology

Semen cryopreservation feasibility

Between 2009 and 2023, we identified 57 male patients, aged between 18 and 50 years (median range 37 years), admitted to the Department of Hematology, Policlinico Tor Vergata of Rome, who were eligible for semen cryopreservation.

Among these, 16 (28%) underwent fertility preservation procedures. In the 41 patients (72%) for whom cryopreservation was not performed, the reasonsfor not proceeding were: refusal of this procedure by the patient (because he is already a father or not wish for paternity) (12,[29%]), the clinical need to start antileukemic therapy immediately (22, [54%]), infection ongoing (1, [7%]) and early death (5, [7%]).

Approach to fertility preservation in AL patients

Most of the patients referred to the Laboratory of Seminology – Sperm Bank “Loredana Gandini had TC and lymphomas (HL and NHL). Between 1996 and 2023, we identified 56 AL patients who performed semen cryopreservation at our Center. Over these years, we observed a remarkable increase in the number of cryopreservations performed. When divided into three periods (1996–2005, 2006–2014, 2015–2023) we observed that the number of AL patients increased from 6 in the first period, 22 in the second, and 28 in the third. In the case of lymphomas and testicular cancer, the numbers are significantly higher. For lymphomas the number of patients increased from 348, 655 and finally 735, while for testicular cancer the number rose from 625 in the first period, later 1245 and finally 1438 patients (Fig. 6).

Fig. 6.

Fig. 6

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Number of patients with AL, TC, LH and NHL who performed semen cryopreservation at our center “Loredana Gandini” Sperm Bank - Department of Experimental Medicine -“Sapienza” University of Rome 1996 to 2023. AL: acute leukemia; TC: testicular cancer; HL: Hodgkin’s lymphoma; NHL: Non-Hodgkin’s lymphoma

Discussion

The improvement in the 5-year survival rate for AL patients has led them to look beyond cancer to a reproductive life and to the decision to have their own biological child. However, cancer may affect male fertility even before anti-cancer treatments and in addition some of these treatments can impair spermatogenesis, reduce fertility, and even lead to permanent azoospermia [9]. Several studies have explored the impact of different types of cancer on male reproductive health but very few studies focused about the effect of AL on semen likely due to the rarity of the incidence of AL and the urgency of starting treatment [3–8]. Our experience at the “Loredana Gandini” Sperm Bank - Department of Experimental Medicine - “Sapienza” University of Rome confirmed these trends. The center has been involved in cryopreservation of semen and testicular tissue since 1996; during these years among approximately 6500 patients who cryopreserved, 49% were affected by TC and 29% by hematological neoplasia (lymphomas, AL, chronic leukemias and myeloma) (Fig. 7). These data show a low percentage of cryopreservation of patients with AL, representing only 2,7% among hematological diseases. The disease’s aggressiveness could have a negative impact on semen quality. Several factors may be involved in the impact of leukemia because the disease may evoke a systemic response of the body mediated by cytokines and other factors secreted by tumor cells and immune system. The imbalance in testicular cytokine and growth factors may also impair the process of spermatogenesis. Moreover, physical and emotional stress linked to cancer diagnosis can impact on semen quality through a dysregulation of hormone levels. Finally, decline of the general state and hyperthermia could be additional pathophysiological mechanisms responsible for the impaired spermatogenesis in AL patients [9]. Another important issue that could be involved in the alteration of semen quality in these patients is thesuspected infiltration of leukemia cells into the testis and their possible effect on immune and non-immune testicular cell function [9]. Auger et al. (2016) compared semen quality in cancer patients including those with TC and leukemia (both acute and chronic), to fertile men and partners of pregnant women. TC and leukemia patients had the lowest semen characteristics with sperm production about one quarter of that in control groups. Leukemia patients present the highest rates of azoospermia and the lowest rates of normozoospermia likely due to altered general state and hyperthermia. In their opinion, semen quality may be better in chronic leukemia than in the AL due to the more severe clinical course of AL. However, the study did not distinguish between acute and chronic leukemia [8]. Hotaling et al. (2013) evaluated semen quality before and after cryopreservation in patients with various types of cancer identifying that myeloid and lymphoid leukemia patients showed a significant decrease of semen parameters. In particular, TC and lymphoid leukemia patients had a significant test-thaw total motile count reduction compared with control. Authors suggest that the negative correlation between hematologic cancer and semen parameters could be related to both symptoms such as fevers and alteration in cytokine or growth factor expression affecting spermatogenesis. However, the study did not specify whether cases were acute or chronic therefore data on only AL are not available [17]. Johnson et al. (2013) performed a retrospective cohort study that reviewed sperm banking by cancer patients and infertile men. Their results highlight those patients with leukemia had the poorest samples, with lower pre-thaw count and motility and highest discard rates due to death, comparing to all other cancers. In author’s opinion, cancer patients have an intrinsic suppression of spermatogenesis, but the mechanisms remain unclear. Also, in this study, results about semen quality of only AL patient were not provided [18].

Fig. 7.

Fig. 7

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Percentage distribution of diseases for which cryopreservations were performed at center “Loredana Gandini” Sperm Bank - Department of Experimental Medicine -“Sapienza” University of Rome 1996 to 2023

To our knowledge, few studies focus exclusively on AL. In fact, we can note that in hematological groups of the literature studies, leukemia patients represent a small proportion. This could be due to the pessimistic view of the oncologist about AL prognosis, reducing referrals for sperm banking [19]. Results in literature about semen parameters are discordant and based on limited samples. In our study, we analyzed semen parameters before antineoplastic treatment exclusively in AL patients. Our results showed that the mean baseline characteristics of ALL patients were around the 25° percentile, while those of AML patients were around the 50° percentile according to WHO 2021 criteria. None of the patients were azoospermic the day of cryopreservation and no significant differences were observed between AML and ALL patients (Table 1). Overall, our data highlight good semen quality of AL patients at the time of cryopreservation, regardless of the type of leukemia (ALL or AML). This data is essential because it gives these patients a real chance of having children in the future, especially in light of therapeutic advancements and the increased survival rates [10, 11]. Very often these patients are not offered the right level of information about cryopreservation of semen samples before starting therapies, likely due to the urgency of starting therapy in a compromised clinical context. Our post-treatment data, although limited, suggest a trend towards reduced progressive motility, but the small follow-up cohort prevents robust analyses and only gives a picture of the progression of semen parameters. Few studies have addressed post-treatment semen quality in newly diagnosed adult AL patients; most focus on long-term survivors of childhood AL or middle-aged populations, often using varied methods of assessing patients’ reproductive health (i.e. self-report questionnaire, hormonal parameters, ultrasound examination and semen parameters) [20–24]. Despite this, literature support our findings on the gonadotoxic effect of AL therapies. In our experience, fertility preservation in male AL patients is possible in about 30% of cases in line with other experiences. Noetzli et al. selected 145 of 459 (31%) patients as eligible for fertility preservation based on their institutional inclusion criteria. The procedure was attempted in 34 (23%) and successful in 29 (20%) over a 10-year period from 2002 to 2012 [25]. Both Noetzli et al.‘s study and ours have the limitation of being retrospective studies, spanning a long period of time [25]. During this time, numerous advances have been made in the knowledge and management of AL. First, there has been a change in the paradigm that treatment, in AML, is to be started immediately after diagnosis. Except in critical cases of coagulopathy, leukostasis, or neutropenic fever, in which delays in AML treatment should be avoided, in most cases slightly postponing the start of antileukemic treatment does not seem to impact overall survival [26, 27]. Indeed, waiting for genetic/cytogenetic and fitness information may better guide the choice of treatment [28]. This window also allows for discussion and planning fertility preservation. Even for ALL patients, in most cases, it is possible to wait, given the importance of acquiring genetic/cytogenetics information and the possibility to obtain a disease control with steroid pre-phase up to 5 days [29]. In recent years, prognosis for AL patients has improved significantly thanks to the introduction of tyrosine kinase inhibitors in Philadelphia chromosome-positive ALL and pediatric asparaginase-based approaches for young adults with the Philadelphia chromosome-negative subgroup [30]. Currently, in adolescents and young adults, survival rates are between about 65-70% and are even higher for patients with a favorable risk profile, including a deep response to treatment [31]. Furthermore, advances in immunotherapy and other targeted treatments are enabling more personalized and less toxic approaches further improving outcomes. The modern therapeutic strategies, the better knowledge of baseline genetics features, and the possibility of assessing with increasingly sophisticated methods the response to treatment, is also changing the prognosis in AML patients.

Although our study is limited by the small number of patients and incomplete clinical data it is, to the best of our knowledge, the first to evaluate semen characteristics exclusively in AL patients, distinct from other hematological cancer. Our results support the need for greater awareness among onco-hematologists about cryopreservation of semen for patients with AL to ensure that they can become parents in the future and face the treatment course with greater confidence.

Author contributions

MIDP, DP designed the study; MIDP, AB drafted the manuscript; EB, LF, DK, GP, IT, SC, CM collected clinical data; SB, LC, GC, ACC, SDC collected andrological data; SDC, AB collected fertility data; FP performed statistical analysis; SDC, DP. AB, MIDP analyzed results; FL, AV provided supervision; MIDP, DP, FL performed.revision and editing. All authors reviewed the manuscript.

Funding

This work was supported by grants from the Italian Ministry of Education and Research (MIUR-PRIN 2022EHN49M _003) and the “Sapienza” University of Rome - Faculty of Medicine.

Data availability

All relevant data are included in this article. For additional data inquiries, a request can be directed to the corresponding author.

Declarations

Ethics approval

This study was approved by Policlinico Umberto I Ethics Committee (Prot. 0671/2024).

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Alessandra Buonacquisto and Maria Ilaria Del Principe contributed equally to this work.

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