Oocyte cryopreservation during blinatumomab treatment for acute lymphoblastic leukemia: A case report
Article information
Abstract
Fertility preservation (FP) in female patients with B-cell acute lymphoblastic leukemia (B-ALL) is challenging because the urgent initiation of chemotherapy often limits the time available for FP. Oocyte cryopreservation (OC) is the most established method for female FP; however, it requires ovarian stimulation, which may not be feasible in this clinical context. We report successful OC during blinatumomab treatment in a 19-year-old woman with newly diagnosed Philadelphia chromosome-negative B-ALL. She received one course of conventional chemotherapy with a gonadotropin-releasing hormone agonist, followed by one course of blinatumomab as induction therapy before allogeneic hematopoietic cell transplantation. Immediately after completion of blinatumomab, ovarian stimulation was initiated. After 13 days of stimulation, 22 oocytes were retrieved, of which 16 mature oocytes were cryopreserved. This case suggests that OC during blinatumomab treatment may represent a feasible FP strategy while maintaining intensive oncologic therapy.
Introduction
The incidence of acute lymphoblastic leukemia (ALL) has increased globally among adolescents and young adults (AYA), underscoring the importance of fertility preservation (FP) in this population [1]. Cytotoxic chemotherapy and allogeneic hematopoietic cell transplantation (allo-HCT) often result in irreversible premature ovarian insufficiency (POI) [2]. Therefore, FP should be discussed before the initiation of anticancer therapy [2,3]. Oocyte cryopreservation (OC) is the most established FP method but requires several weeks for ovarian stimulation. Ovarian tissue cryopreservation (OTC) is an alternative option; however, it is subject to varying regulatory frameworks and carries a potential risk of leukemic cell reintroduction [3,4]. Determining the optimal timing of FP in ALL is challenging because of the urgency of chemotherapy initiation, which leaves patients with limited opportunities for FP prior to treatment.
Blinatumomab, a bispecific T-cell engager that induces apoptosis and lysis of leukemic blasts, has emerged as a treatment for relapsed, refractory, or measurable residual disease (MRD)-positive B-cell ALL (B-ALL) [5]. However, the safety and feasibility of FP during blinatumomab therapy remain unclear. To date, only one case has reported controlled ovarian stimulation (COS) during blinatumomab treatment [6]. We present a case of a newly diagnosed Philadelphia chromosome-negative (Ph−) B-ALL AYA patient who successfully underwent OC after one cycle of blinatumomab.
Case report
A 19-year-old nulliparous woman was diagnosed with Ph− B-ALL. At initial presentation, complete blood count revealed a markedly elevated white blood cell count of 169.7×10³/µL (93% blasts), a hemoglobin level of 6.9 g/dL, and a platelet count of 77×10³/µL. On the day of bone marrow aspiration to confirm the diagnosis, a gonadotropin-releasing hormone agonist (GnRH-a; triptorelin 3.75 mg every month) was administered for FP prior to chemotherapy [7]. Bone marrow examination demonstrated 97.6% lymphoblasts positive for CD13 (bright), CD34, CD33, CD66c/CD123, CD81, CD304/CD73, CD19, CD38 (intermediate), and lacks expression of terminal deoxynucleotidyl transferase (TdT) (dim). All myeloid and T-lineage antigens tested negative except for CD13 and CD33. B-ALL with aberrant expression of CD13 and CD33 was confirmed. Cytogenetic analysis demonstrated a karyotype of 46, XX, t(12;17)(p13;q21)[16]/46, XX[4]. Induction chemotherapy with modified vincristine, prednisolone, daunorubicin, and L-asparaginase (mVPDL; vincristine, 2 mg/day on days 1 and 8; prednisolone, 60 mg/m²/day on days 1–14; daunorubicin, 90 mg/m²/day on days 1–3; and L-asparaginase, 4,000 KU/m²/day on days 17–28), along with intrathecal methotrexate (15 mg), was initiated immediately. After achieving a first complete remission (CR) with MRD positivity by flow cytometry (1.6%) (MRD grade 1, 0%≤ to <0.01%), the patient received a course of blinatumomab (9 μg/day for the first 7 days, followed by 28 μg/day from day 8 to day 28), resulting in a second CR with MRD negativity (MRD grade 4, 1%≤ to <5%).
Although the potential effects of blinatumomab on gonadal toxicity and future chromosomal abnormalities in embryos remain unknown, FP was planned because the patient was expected to undergo allo-HCT after blinatumomab bridging therapy, which is associated with a high risk of POI and infertility. OTC was not considered because of the risk of tumor cell contamination and because it has not yet been institutionally or legally established in Korea. After thorough counseling and the provision of informed consent, OC was initiated according to the GnRH-a long protocol because the patient had been receiving monthly GnRH-a injections for FP and was considered to be in a state of pituitary downregulation. Baseline hormone levels were as follows: follicle-stimulating hormone, 3.8 mIU/mL; luteinizing hormone, 0.74 mIU/mL; and serum estradiol, 12.7 pg/mL. Her anti-Müllerian hormone level was preserved, measuring 1.29 ng/mL before mVPDL and 1.72 ng/mL afterward. Transvaginal ultrasonography demonstrated an antral follicle count of 10 and a thin endometrium. Human menopausal gonadotropin was administered daily at 300 IU for 13 days until ovulation was triggered. When the follicles reached a mean diameter of 18 to 20 mm, recombinant human chorionic gonadotropin was administered to trigger ovulation, and oocyte retrieval was performed 36 hours later. A total of 22 oocytes were retrieved, of which 16 were mature and successfully cryopreserved, yielding a maturation rate (mature oocytes/retrieved oocytes) of 72.7%. No procedure-related adverse events were observed. She was scheduled to undergo a second cycle of blinatumomab followed by allo-HCT from a matched sibling donor. The treatment course for ALL and the COS schedule are shown in Figure 1.
Treatment course of acute lymphoblastic leukemia and schedule of controlled ovarian stimulation (COS). COS was initiated after the required 2-week blinatumomab resting period following hematologic evaluation. A total of 16 mature oocytes were cryopreserved. No procedure-related adverse events were observed. In total, an additional 3 weeks were required for gynecologic assessment and oocyte retrieval. GnRH-a, gonadotropin-releasing hormone agonist; mVPDL, modified vincristine, prednisolone, daunorubicin, and L-asparaginase; IT MTX, intrathecal methotrexate; OPU, ovum pick-up; CR, complete remission; MRD, measurable residual disease.
The mature oocytes were classified as normal or abnormal on the basis of morphological criteria. Normal oocytes were characterized by clear cytoplasm with fine, homogeneous granularity; a round or ovoid first polar body; a smooth surface; a perivitelline space of normal size; and a colorless zona pellucida with a regular shape [8]. Oocyte dysmorphisms were categorized as cytoplasmic abnormalities, extracytoplasmic abnormalities, shape abnormalities, or multiple abnormalities. In this case, five oocytes (31%) were normal, whereas seven showed cytoplasmic abnormalities, two had extracytoplasmic abnormalities, and two exhibited multiple abnormalities. Representative oocyte morphologies are shown in Figure 2.
Normal and dysmorphic oocytes viewed under a microscope. (A) A normal oocyte composed of clear cytoplasm (bold arrow) with fine, homogeneous granularity, a round or ovoid first polar body (PB; asterisk), a smooth surface, a perivitelline space (PVS; narrow arrow) of normal size, and a colorless zona pellucida (ZP; white arrow) with a regular shape. (B) A dysmorphic oocyte exhibiting both cytoplasmic and extracytoplasmic abnormalities. Cytoplasmic granulation (bold arrow) is observed, along with fragments and debris within a large PVS (narrow arrow).
This case report was approved by the Asan Medical Center Institutional Review Board (2025-1218).
Discussion
We report the first Korean case of successful OC performed during blinatumomab treatment in a patient with B-ALL. COS during the blinatumomab resting period resulted in the retrieval of morphologically assessable mature oocytes. To our knowledge, this is the first report to describe both the feasibility of OC and oocyte morphology during blinatumomab therapy.
Cytotoxic chemotherapy for hematologic malignancies is known to impair ovarian reserve through direct follicular toxicity and indirect mechanisms [9]. Although standard ALL regimens are considered less gonadotoxic, subsequent allo-HCT using high-dose alkylating agents is strongly associated with POI and infertility. Even when menstrual function recovers, significantly diminished ovarian reserve has been observed after treatment [3]. Because oocytes do not regenerate after birth, FP before gonadotoxic therapy is essential, particularly in AYA patients [10].
Bispecific antibodies for cancer therapy have been developed rapidly with diverse structures and target combinations; however, their effects on ovarian toxicity and future fertility remain unknown. To date, no clinical trials or reports have evaluated the gonadal toxicity of blinatumomab. Given the low abundance of B and T lymphocytes in ovarian tissue, blinatumomab may theoretically be less gonadotoxic than conventional chemotherapy [6,11]. In our case, seven oocytes showed cytoplasmic abnormalities, and two exhibited multiple abnormalities. Although oocyte morphology does not always correlate with chromosomal integrity, cytoplasmic abnormalities may be associated with reduced embryo quality [12-14]. These oocytes may therefore be associated with lower fertilization or implantation rates; however, it remains unclear whether this finding is attributable to ALL treatment or to the underlying disease itself, warranting further investigation.
Currently, there are no guidelines regarding the optimal timing of COS for patients with hematologic malignancies during treatment. Because these diseases often require urgent treatment and are frequently accompanied by low absolute neutrophil and platelet counts, COS at initial diagnosis is usually not feasible. In newly diagnosed ALL in particular, immediate treatment initiation is essential, leaving only a very narrow window for FP. To date, only a few case reports have described COS between induction and consolidation chemotherapy in patients with leukemia. Only one report has described COS during blinatumomab treatment for ALL, in which two patients underwent COS during the resting phase without treatment delay; however, only two and three oocytes were retrieved, respectively [6]. This poor outcome was likely attributable to prior first-line chemotherapy with high-dose cyclophosphamide, which resulted in diminished ovarian reserve. Therefore, preceding treatment with less gonadotoxic chemotherapy may optimize the use of blinatumomab for FP, as demonstrated in our case.
In this case, FP was performed during the blinatumomab bridging period before planned allo-HCT, when the patient had achieved remission and her disease status was stable. Given the absence of established guidelines, determining the optimal timing of COS was challenging. COS was initiated after the required 2-week blinatumomab resting period following hematologic evaluation, and an additional 3 weeks were required for gynecologic assessment and oocyte retrieval. This delay was carefully considered by the hematology team because the patient had achieved remission and remained clinically stable. The patient subsequently proceeded with the planned second cycle of blinatumomab and allo-HCT without complications. Individualized multidisciplinary planning and thorough counseling remain essential to balance FP with timely leukemia treatment.
Notes
Conflict of interest
No potential conflict of interest relevant to this article was reported.
Acknowledgments
The authors thank the patient for granting permission to publish this case.
Author contributions
Conceptualization: JHK, JYH. Methodology: JHK. Formal analysis: JHL, JHK. Data curation: JHL, JWL, IKJ, EP. Project administration: JHK. Visualization: JHL, JWL, IKJ, EP. Software: JHL, JHK. Validation: JHK, JYH. Investigation: JHL, SYJ. Supervision: JHK. Writing-original draft: JHL, JHK, JYH, . Writing-review & editing: JHK, JYH. Approval of final manuscript: JHL, JHK, JYH, SYJ, JWL, IKJ, EP.