Successful fatherhood of males with tyrosine kinase inhibitor-resistant chronic myeloid leukemia taking olverembatinib

Abstract

As life expectancy in patients with chronic myeloid leukemia (CML) approaches that of the general population, fertility preservation has become a critical quality-of-life consideration, especially for younger patients. Although third-generation (3G) tyrosine kinase inhibitors (TKIs), such as olverembatinib, demonstrate potent efficacy against TKI-resistant disease, their reproductive safety profiles remain largely undefined. We report two TKI-resistant male patients who achieved sustained deep molecular responses with olverembatinib and who subsequently conceived healthy offspring with their partners. These cases provide clinical evidence that olverembatinib exposure does not preclude normal male fertility or healthy offspring, emphasizing the need for systematic reproductive safety data on 3G TKIs.

Introduction

The successive introduction of tyrosine kinase inhibitors (TKIs), including third-generation (3G) TKIs, has dramatically increased the survival rates of patients with chronic myeloid leukemia (CML) [1–4]. The normalization of life expectancy has led to an increasing focus on quality-of-life issues, including fertility. Approximately 20% of individuals diagnosed with CML in Western countries are younger than 45 years, with a slight male predominance. Notably, the median age of CML onset in Asian populations is 10 to 15 years younger than that in Western populations, making fertility a significant clinical concern in this group [5].

A few studies have reported reduced sperm counts and abnormal sperm morphology after several months of TKI exposure [6]. Some data have suggested that potential gonadotoxic effects are mediated by disruption of the hypothalamic–pituitary–gonadal axis. However, preclinical studies and limited clinical data have not consistently demonstrated deleterious effects of TKIs on male fertility, partner pregnancy outcomes, or postnatal development [7, 8].

Although the efficacy and tolerability of 3G TKIs have been well characterized, their reproductive safety profile remains largely undefined. Olverembatinib is a novel 3G TKI with potent activity against TKI-resistant CML and Philadelphia chromosome–positive acute lymphoid leukemia [1, 9, 10]. Preclinical data on olverembatinib have revealed that its administration to male rats induces testicular toxicity, characterized by seminiferous tubule atrophy and degeneration of the spermatogenic epithelium. Additionally, the weights of seminal vesicles and coagulating glands decreased in treated animals, and the incidence of sperm morphological defects increased. We report two cases of TKI-resistant male patients who achieved deep molecular responses with olverembatinib and subsequently fathered healthy offspring.

Case report

Case 1

In May 2007, a 15-year-old boy presented with a 1-week history of abdominal discomfort and a palpable left upper-quadrant mass. The laboratory work-up revealed a white blood cell count of 28 × 10⁹/L and a platelet count of 300 × 10⁹/L, and splenomegaly was confirmed radiologically. He was diagnosed with chronic-phase CML (CML-CP) and was initially treated with traditional Chinese medicine for 2 years, followed by treatment with interferon-α for more than 2 years. Beginning in June 2012, he received imatinib (400 mg qd), but he did not achieve a cytogenetic response at 6 months and switched to nilotinib (300 mg bid). In December 2015, T315I and F359V mutations were detected by Sanger sequencing. At this point, he began receiving 100 mg of dasatinib qd. In May 2016, only the T315I mutation was detected, and a cytogenetic analysis revealed 46,XY, t(9;22)(q34;q11.2) [6]/46,XY[14]. He enrolled in the phase I trial of HQP1351 (olverembatinib) in September 2016. The initial dosage was 1 mg every other day, which increased and reached a dosage of 30 mg every other day by November 2017. He achieved a complete cytogenetic response (CCyR) at 3 months on olverembatinib (30 mg qod) therapy and a major molecular response (MMR) at 6 months. Adverse events (AEs) included hyperpigmentation of the face and upper limbs, hypertension (grade 1), hypertriglyceridemia (grade 1), diminished libido (grade 1), and gynecomastia (grade 1), as assessed by the Common Terminology Criteria for Adverse Events (CTCAE) guidelines. In June 2022, following 69 months of olverembatinib therapy (30 mg every other day), when he was 30 years old, his 29-year-old nulligravida wife spontaneously conceived their first child. The pregnancy proceeded without complications, despite the absence of a preconception semen analysis for the patient. A healthy male infant was delivered by elective cesarean section at 38 weeks and 5 days gestation, with a birth weight of 3.1 kg and an Apgar score of 10 at both 1 and 5 min. The child, who is currently 2 years and 4 months old, demonstrates growth and development consistent with age-appropriate milestones.

Case 2

On September 12, 2014, a 27-year-old man was referred for marked leukocytosis detected during routine health screening. Laboratory values included a white blood cell count of 221 × 10⁹/L and a platelet count of 384 × 10⁹/L. Bone marrow aspiration examination revealed a karyotype of 46,XY, t(9;22)(q34;q11) [16] by G-banding, with the BCR::ABL1 transcript level quantified at 60% (IS). He was diagnosed with CML-CP with a high Sokal score and intermediate ELTS score and received 400 mg of imatinib once daily beginning on September 20, 2014. He switched to nilotinib (400 mg twice daily) after 7 months on imatinib therapy because of a BCR::ABL1 (IS) level > 10% and switched to dasatinib (100 mg daily) after 30 months on nilotinib therapy because of consistent BCR::ABL1 levels above 10%. On November 13, 2019, the Q252H mutation was detected by Sanger sequencing. The patient enrolled in the phase I trial of HQP1351 (olverembatinib) at an initial dosage of 40 mg every other day on December 2, 2019, and he achieved an MMR at 3 months and an MR^4.5 at 18 months. He experienced diminished libido, but a preconception semen analysis confirmed normal sperm motility. In June 2024, following 55 months of olverembatinib therapy (40 mg every other day), when he was 37 years old, the patient’s 31-year-old wife conceived spontaneously. A healthy female neonate was delivered via elective cesarean section at 39 weeks and 2 days of gestation, with a birth weight of approximately 3.2 kg and an Apgar score of 10 at both 1 and 5 min. This event marked the couple’s first live birth, with no history of miscarriages or obstetric complications. At three months of age, the infant demonstrated normal growth and developmental milestones.

Discussion

This report describes two males with TKI-resistant BCR::ABL1 mutations who successfully fathered children while on olverembatinib treatment, contributing to the limited data concerning its reproductive safety. Despite prolonged high-dose olverembatinib exposure, spermatogenesis was unaffected in one patient, and no teratogenic effects or neonatal complications occurred after paternal exposure. However, prospective studies are needed to further investigate these effects.

In male animal models, several tyrosine kinase inhibitors (TKIs), including imatinib, dasatinib, ponatinib and olverembatinib, have been shown to impair spermatogenesis. These agents can penetrate the blood–testis barrier, resulting in testicular histopathological alterations characterized by seminiferous epithelial thinning, decreased spermatid numbers, and increased sperm morphological abnormalities. The primary mechanism involves the inhibition of critical signaling pathways (e.g., c-Kit and ABL) that are vital for germ cell proliferation, differentiation, and survival. Additionally, certain TKIs may interfere with the hypothalamic–pituitary–gonadal axis, causing reduced testosterone levels that further compromise reproductive function. However, clinical evidence from human studies remains inconsistent [11]. In our study, olverembatinib, a highly potent inhibitor of ABL1, KIT, PDGFR, and SRC kinases, was administered to patients for 5.5 and 8.5 years without the occurrence of overt oligospermia or asthenozoospermia. The partner of patient 1 conceived naturally, although no semen analysis was performed for patient 1, whereas patient 2 had normal sperm motility in a preconception analysis. Despite prior TKI regimens (imatinib, nilotinib, and dasatinib) and libido reduction, both patients fathered healthy infants, which is consistent with registry data showing no increase in miscarriage or congenital anomaly rates with paternal TKI exposure. Both infants were born at term and had normal birth weights and Apgar scores, and no malformations were detected early in development; these findings are the same as those of previous studies of other TKIs [12, 13]. A previous study revealed that the incidence of sexual dysfunction was 23% in patients receiving 30 mg of olverembatinib every other day and 18% in those receiving 40 mg qod [10]. However, olverembatinib appears to be devoid of transgenerational teratogenic effects. Animal studies suggest the occurrence of endocrine disruption (e.g., gynecomastia and low testosterone), and both patients experienced reversible gynecomastia and decreased libido in response to olverembatinib but achieved natural conception. This highlights that human outcomes may differ from those of rodent models [11]. The study limitations include a small sample size and a lack of longitudinal semen analyses, hormonal profiling, and sperm DNA assessments. These cases indicate that olverembatinib may not compromise male fertility or fetal safety during active therapy, but systematic surveillance is recommended for confirmation and counseling.

Author contributions

All the authors contributed to the study conception and design. Lu Yu wrote the first draft of the manuscript. Qian Jiang revised and approved the final version of the manuscript.

Funding

This study was funded by the National Natural Science Foundation of China (Nos. 81970140 and 82370161).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Consent to participate

Informed consent was obtained from all the individual participants included in the study.

Consent to publish

The participants consented to the submission of the case report to the journal.

Competing interests

The authors declare no competing interests.